Viral polymerase inhibitors

ABSTRACT

A compound of the formula I:                    
     wherein: 
     X is CH or N; Y is O or S; Z is OH, NH 2 , NMeR 3 , NHR 3 ; OR 3  or 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents; A is N, COR 7  or CR 5 , wherein R 5  is H, halogen, or (C 1-6 ) alkyl and R 7  is H or (C 1-6  alkyl), with the proviso that X and A are not both N; R 6  is H, halogen, (C 1-6  alkyl) or OR 7 , wherein R 7  is H or (C 1-6  alkyl); 
     R 1  is selected from the group consisting of 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C 1-3 )alkyl, (C 2-6 )alkenyl, phenyl(C 2-6 )alkenyl, (C 3-6 )cycloalkyl, (C 1-6 )alkyl, CF 3 , 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, wherein said heterocycle, phenyl, phenyl(C 2-6 )alkenyl and phenyl(C 1-3 )alkyl), alkenyl , cycloalkyl, (C 1-6 )alkyl, and heterobicycle are all optionally substituted with from 1 to 4 substituents; 
     R 2  is selected from (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-3 )alkyl, (C 6-10 )bicycloalkyl, adamantyl, phenyl, and pyridyl, all of which is optionally substituted with from 1 to 4 substituents; 
     R 3  is selected from H, (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-6 )alkyl, (C 6-10 )aryl (C 6-10 )aryl(C 1-6 )alkyl, (C 2-6 )alkenyl, (C 3-6 )cycloalkyl(C 2-6 )alkenyl, (C 6-10 )aryl(C 2-6 )alkenyl, N{(C 1-6 ) alkyl} 2 , NHCOO(C 1-6 )alkyl(C 6-10 )aryl, NHCO(C 6-10 )aryl, (C 1-6 )alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S; 
     wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents; n is zero or 1; or a detectable derivative or salt thereof. 
     The compounds of the invention may be used as inhibitors of hepatitis C virus replication. 
     The invention further provides a method for treating or preventing hepatitis C virus infection.

RELATED APPLICATIONS

This application is a divisional of Ser. No. 09/898,297, filed Jul. 3,2001, which is incorporated by reference in its entirety.

Benefit of U.S. Provisional Application Serial No. 60/216,084, filed onJul. 6, 2000, U.S. Provisional Application Serial No. 60/274,374, filedon Mar. 8, 2001, and U.S. Provisional Application Serial No. 60/281,343,filed on Apr. 5, 2001, are hereby claimed, each of which is incorporatedby reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to inhibitors of RNA dependent RNA polymerases,particularly those viral polymerases within the Flaviviridae family, andmore particularly the NS5B polymerase of HCV.

BACKGROUND OF THE INVENTION

About 30,000 new cases of hepatitis C virus (HCV) infection areestimated to occur in the United States each year (Kolykhalov, A. A.;Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74:2046-2051*). HCV is not easily cleared by the hosts' immunologicaldefences; as many as 85% of the people infected with HCV becomechronically infected. Many of these persistent infections result inchronic liver disease, including cirrhosis and hepatocellular carcinoma(Hoofnagle, J. H.; 1997; Hepatology 26: 15S-20S*). There are anestimated 170 million HCV carriers world-wide, and HCV-associatedend-stage liver disease is now one of the leading cause of livertransplantation. In the United States alone, hepatitis C is responsiblefor 8,000 to 10,000 deaths annually. Without effective intervention, thenumber is expected to triple in the next 10 to 20 years. There is novaccine to prevent HCV infection. Prolonged treatment of chronicallyinfected patients with interferon or interferon and ribavirin is theonly currently approved therapy, but it achieves a sustained response infewer than 50% of cases (Lindsay, K. L.; 1997; Hepatology 26: 71S-77S*,and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology 26:108S-111S*). HCV belongs to the family Flaviviridae, genus hepacivirus,which comprises three general of small enveloped positive-strand RNAviruses (Rice, C. M.; 1996; “Flaviviridae: the viruses and theirreplication”; pp. 931-960 in Fields Virology; Fields, B. N.; Knipe, D.M.; Howley, P. M. (eds.); Lippincott-Raven Publishers, Philadelphia Pa.*). The 9.6 kb genome of HCV consists of a long open reading frame (ORF)flanked by 5′ and 3′ non-translated regions (NTR's). The HCV 5′ NTR is341 nucleotides in length and functions as an internal ribosome entrysite for cap-independent translation initiation (Lemon, S. H.; Honda,M.; 1997; Semin. Virol. 8: 274-288*). The HCV polyprotein is cleaved co-and post-translationally into at least 10 individual polypeptides (Reed,K. E.; Rice, C. M.; 2000; Curr. Top. Microbiol. Immunol. 242: 55-84*).The structural proteins result from signal peptidases in the N-terminalportion of the polyprotein. Two viral proteases mediate downstreamcleavages to produce non-structural (NS) proteins that function ascomponents of the HCV RNA replicase. The NS2-3 protease spans theC-terminal half of the NS2 and the N-terminal one-third of NS3 andcatalyses cis cleavage of the NS2/3 site. The same portion of NS3 alsoencodes the catalytic domain of the NS3-4A serine protease that cleavesat four downstream sites. The C-terminal two-thirds of NS3 is highlyconserved amongst HCV isolates, with RNA-binding, RNA-stimulated NTPase,and RNA unwinding activities. Although NS4B and the NS5A phosphoproteinare also likely components of the replicase, their specific roles areunknown. The C-terminal polyprotein cleavage product, NS5B, is theelongation subunit of the HCV replicase possessing RNA-dependent RNApolymerase (RdRp) activity (Behrens, S. E.; Tomei, L.; DeFrancesco, R.;1996; EMBO J. 15: 12-22*; and Lohmann, V.; Körner, F.; Herian, U.;Bartenschlager, R.; 1997; J. Virol. 71: 8416-8428*). It has beenrecently demonstrated that mutations destroying NS5B activity abolishinfectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik, K.;Feinstone, S. M.; Rice, C. M.; 2000; J. Virol. 74: 2046-2051*).

* incorporated herein by reference

The development of new and specific anti-HCV treatments is a highpriority, and virus-specific functions essential for replication are themost attractive targets for drug development. The absence of RNAdependent RNA polymerases in mammals, and the fact that this enzymeappears to be essential to viral replication, would suggest that theNS5B polymerase is an ideal target for anti-HCV therapeutics.

WO 00/06529 reports inhibitors of NS5B which are α, γ-diketoacids.

WO 00/13708, WO 00/10573, and WO 00/18231 report inhibitors of NS5Bproposed for treatment of HCV.

SUMMARY OF THE INVENTION

The present invention reduces the difficulties and disadvantages of theprior art by providing a novel class of compounds useful for thetreatment and prevention of hepatitis C virus (HCV) infection. Theaforesaid compounds have been found to inhibit an RNA dependent RNApolymerase encoded by HCV.

In a first aspect, the invention provides a compound of formula I:

wherein:

X is CH or N;

Y is O or S;

Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from:

COOH and —O-(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH;

A is N, COR⁷ or CR⁵, wherein R⁵ is H, halogen, or (C₁₋₆) alkyl and R⁷ isH or (C₁₋₆ alkyl), with the proviso that X and A are not both N;

R⁶ is H, halogen, (C₁₋₆ alkyl) or OR⁷, wherein R⁷ is H or (C₁₋₆ alkyl);

R¹ is selected from the group consisting of 5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N, and S, phenyl,phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₁₋₆)alkyl, CF₃, 9- or 10-membered heterobicycle having 1 to 4heteroatoms selected from O, N and S,

wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl , cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂;

R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from

halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl and OH;

R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆)alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S;

wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are alloptionally substituted with from 1 to 4 substituents selected from: OH,COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₁₋₆)alkyl-hydroxy, phenyl,benzyloxy, halogen, (C₂₋₄)alkenyl, (C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, andcarboxy(C₂₋₄)alkenyl, 5- or 6-membered heterocycle having 1 to 4heteroatoms selected from O, N and S, said heterocycle being optionallysubstituted with from 1 to 4 substituents selected from:

(C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH, NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆ alkyl)₂, wherein p is an integerfrom 1 to 4;

9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected fromO, N and S, said heterobicycle being optionally substituted with from 1to 4 substituents selected from:

halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, triazolyl, (C₁₋₄)alkoxy,cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO-(C₁₋₆)alkyl,—NHCOCOOH, —NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁l₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃;

6- or 10-membered aryl being optionally substituted with from 1 to 4substituents selected from:

halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, nitro, —CONH₂, —COCH₃,(C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, OH, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, triazolyl, (C₁₋₄)alkoxy,cyano, azido, —O—(C₁l₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl,—NHCOCOOH, —NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃;

coumarin, (C₁₋₆)alkyl-amino, di-(C₁₋₆)alkyl-amino, C(halogen)₃,—NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl, —CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH,—CO—NH-alanyl, —(CH₂)_(p)COOH, —OCH₂Ph, —CONHbenzyl, —CONHpyridyl,—CONHCH₂pyridyl, —CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄)alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄)alkyl-N-methylpyrrolidino, —CONH(C₂₋₄) alkyl-(COOH)-imidazole,—CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH, —CONH(C₆₋₁₀) aryl-COOH,—CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆) alkyl-COO(C₁₋₆) alkyl,—CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl—CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from;

COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is an integer from 1 to4;

—CONH(C₆₋₁₀) aryl-5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N and S, said heterocycle being optionally substitutedwith from 1 to 4 substituents selected from:

COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;

—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from:

COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;

—O(CH₂)_(p)tetrazolyl, wherein p is an integer from 1 to 4; and

n is zero or 1;

or a detectable derivative or salt thereof;

with the proviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkylor hydroxyalkyl, then R¹ is not a five membered heterocycle containing Sand N;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR¹ is (C₂₋₁₀)alkyl, (C₃₋₁₀)alkenyl, (C₃₋₆)cycloalkyl or phenyl, then R²is not phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or hydroxyalkyl, then R¹ is not 5-nitro-2-furyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is optionally substituted alkyl or cycloalkyl, then R¹is5-aryl-2-furyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or cycloalkyl, then R¹ is not 6-phenylbenzofuran-2-yl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is n-Pr, then R¹is not 2,3-benzofuranyl or phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is Me, then R¹ is not phenyl or methoxy-2,3-benzofuranyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is Et, then R¹ is not methoxy-2,3-benzofuranyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₈)alkyl, then R¹ is not ethenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is lower alkyl, then R¹ is not substituted or unsubstituted phenyl,heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is lower alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not alkenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl, then R¹ is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl, then R¹ is not (C₅₋₁₅)aryl,(C₂₋₆)alkenyl or (C₃₋₁₀)heteroarylene;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₁₂)alkyl, then R¹ is not phenyl or aryl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or cycloalkyl, then R¹ is not 2-hydroxyphenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=1, thenR¹ is not methyl, ethyl or vinyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=1, thenR¹ is not 5-azabenzimidazol-2-yl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0or 1,and R² is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl then R¹ is not C₁₋₄ alkyloptionally substituted by OH, COOH or halo;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1,R¹ is heteroaryl or phenyl, then R² is not heteroaryl or phenyl;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is (C₁₋₃)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, andfurther substituted with aryl or heteroaryl, n=0 or 1, and R¹ is(C₂₋₁₀)alkyl, (C₃₋₆)cycloalkyl or phenyl, then R² is not optionallysubstituted phenyl;

and with the further proviso that if X is CH, Y is O, Z is NMeR³ or NHR³[wherein R³ is alkyl], n=0, and R² is alkyl, cycloalkyl or aryl, then R¹is not a substituted 2-benzofuryl group;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is alkyl, n=0, and R² is alkyl or cycloalkyl, then R¹ is not asubstituted benzofuryl group or benzofuran-2-yl;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is Me, n=0, and R² is Me, then R¹ is not methoxy-2,3-benzofuranyl;

and with the proviso that if X is CH, Y is O, Z is NHR³ [wherein R³ isalkyl or aryl], n=0, and R² is alkyl not substituted with OH, then R¹ isnot aryl or heterocycle;

and with the further proviso that if X is CH, Y is O, Z is NHR³ [whereinR³ is alkyl, cycloalkyl, aryl or heteroaryl], n=0, and R² is alkyl orcycloalkyl, then R¹ is not aryl, heteroaryl or alkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³ orNMeR³ [wherein R³ is (C₁₋₄)alkyl], n=0, and R² is (C₁4)alkyl, then R¹ isnot phenyl bearing an N-substituted sulfonamido group;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, cycloalkyl, aryl or heterocycle, n=0, and R² isalkyl or cycloalkyl, then R¹ is not 3,4-dialkoxyphenyl,3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is H, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl orbenzyl, n=0, and R² is alkyl, cycloalkyl or hydroxyalkyl, then R¹ is nottetrazolyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl,arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl,n=0, and R² is lower alkyl, then R¹ is not substituted phenyl orheteroaryl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is H, alkyl, phenyl or benzyl, n=0, and R² is (C₁₋₄)alkyl,then R¹ is not phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=0, and R² is alkyl or hydroxyalkyl, then R¹ is not fluoroalkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=0, and R² is alkyl, then R¹ is not alkenyl or aryl; and with thefurther proviso that if X is CH, Y is O, Z is NHR³ [wherein R³ isthiazolyl], n=1, and R² is (C₁₋₈)alkyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, phenyl or heteroaryl, then R¹ is not phenyl,phenyl(C₂₋₄)alkenyl, heteroaryl, heterocycle, (C₁₋₈)alkyl,(C₂₋₆)alkenyl, or (C₃₋₇)cycloalkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=1, and R² is (C₁₋₅)alkyl, then R¹ is not methyl or optionallyhalogenated phenyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂, n=0, andR² is n-Pr, then R¹ is not phenylethenyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂, n=0, andR² is alkyl, then R¹ is not substituted phenyl or naphthyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂,or NHR³wherein R³ is (C₁₋₄)alkyl, benzyl or p-fluorophenylmethyl, n=0, and R²is (C₁₋₄)alkyl, then R¹ is not phenyl substituted with acylamino.

Alternatively, the first aspect of the invention also provides acompound of formula Ia:

wherein:

X is CH or N;

Y is O or S;

Z is OH, NH₂, NMeR³ or NHR³;

and wherein

R¹ is selected from 5- or 6-membered heteroaryl or heterocycle having 1to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl,(C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, 9- or10-atom heterobicycle having 1 to 4 heteroatoms selected from O, N andS,

wherein said heteroaryl, phenyl phenylalkenyl, phenylalkyl, alkenyl,cycloalkyl, (C₁₋₆)alkyl, and heterobicycle are all optionallysubstituted with 1 to 4 substituents selected from: OH, halogen, cyano,phenyl(C₁₋₄)alkoxy, COOH, —OCH₂CONHCH₂Ph, (C₁₋₄)alkyl,—OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy, —OCH₂CO-(morpholino),pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy, —NH(C₂₋₄)acyl,—O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃ and NO₂;

R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from:

halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl and OH;

R³ is selected from (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,and 5- to 10-membered heterocycle having 1 to 4 heteroatoms selectedfrom O, N and S;

wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are alloptionally substituted with from 1 to 4 substituents selected from: OH,COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, phenyl, benzyloxy, halogen,(C₂₋₄)alkenyl, carboxy(C₂₋₄)alkenyl, 5- to 6-membered heterocycle having1 to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to four substituents selected from:

CH₃, CF₃, OH, CH₂COOH and COOH;

9- to 10-membered heterobicycle having 1 to 4 heteroatoms selected fromO, N and S said heterobicycle being optionally substituted with from 1to 4 substituents selected from:

halogen, (C₁₋₃)alkyl, (C₁₋₃)alkoxy, tetrazolyl, COOH, —CONH₂, triazolyl,OH, and —O(C₁₋₃)alkylCOOH; (C₁₋₄)alkoxy, cyano, amino, azido,(C₁₋₆)alkyl-amino, di-(C₁₋₆)alkyl-amino, OPO₃H, sulfonamido, SO₃H,SO₂CH₃, nitro, C(halo)₃, —NH(C₂₋₄)acyl, —NHCOCOOH, —NHCH₂COOH, —NHCONH

 —NHCN, —NHCHO, —NHSO₂CH₃, —NHSO₂CF₃, —NH(C₆₋₁₀)aroyl, —CONH₂,—CO—NH-alanyl, —(CH₂)_(p)COOH, —OCH₂Ph, —O—(C₁₋₆)alkyl COOH,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(CH₃)₂, —CONH(C₂₋₄)alkylmorpholino and—O(CH₂)_(p)tetrazolyl, p being an integer from 1 to 4; and

n is zero or 1; or a salt thereof;

with the proviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkylor hydroxyalkyl, then R¹ is not a five membered heterocycle containing Sand N;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR¹ is (C₂₋₁₀)alkyl, (C₃₋₁₀)alkenyl, (C₃₋₆)cycloalkyl or phenyl, then R²is not phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or hydroxyalkyl, then R¹ is not 5-nitro-2-furyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is optionally substituted alkyl or cycloalkyl, then R¹ is5-aryl-2-furyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or cycloalkyl, then R¹ is not 6-phenylbenzofuran-2-yl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is n-Pr, then R¹ is not 2,3-benzofuranyl or phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is Me, then R¹ is not phenyl or methoxy-2,3-benzofuranyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is Et, then R¹ is not methoxy-2,3-benzofuranyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₈)alkyl, then R¹ is not ethenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is lower alkyl, then R¹ is not substituted or unsubstituted phenyl,heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is lower alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not alkenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl, then R¹ is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₄)alkyl or hydroxy(CO₁₋₄)alkyl, then R¹ is not (C₅₋₁₅)aryl,(C2₆)alkenyl or (C₃₋₁₀)heteroarylene;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is (C₁₋₁₂)alkyl, then R¹ is not phenyl or aryl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0, andR² is alkyl or cycloalkyl, then R¹ is not 2-hydroxyphenyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=1, thenR¹ is not methyl, ethyl or vinyl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=1, thenR¹ is not 5-azabenzimidazol-2-yl;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1,and R² is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl then R¹ is not C₁₋₄alkyloptionally substituted by OH, COOH or halo;

and with the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1,R¹ is heteroaryl or phenyl, then R² is not heteroaryl or phenyl;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is (C₁₋₃)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, andfurther substituted with aryl or heteroaryl, n=0 or 1, and R¹ is(C₂₋₁₀)alkyl, (C₃₋₆)cycloalkyl or phenyl, then R² is not optionallysubstituted phenyl;

and with the further proviso that if X is CH, Y is O, Z is NMeR³ or NHR³[wherein R³ is alkyl], n=0, and R² is alkyl, cycloalkyl or aryl, then R¹is not a substituted 2-benzofuryl group;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is alkyl, n=0, and R² is alkyl or cycloalkyl, then R¹ is not asubstituted benzofuryl group or benzofuran-2-yl;

and with the further proviso that if X is CH, Y is O, Z is NHR³ whereinR³ is Me, n=0, and R² is Me, then R¹ is not methoxy-2,3-benzofuranyl;

and with the proviso that if X is CH, Y is O, Z is NHR³ [wherein R³ isalkyl or aryl], n=0, and R² is alkyl not substituted with OH, then R¹ isnot aryl or heterocycle;

and with the further proviso that if X is CH, Y is O, Z is NHR³ [whereinR³ is alkyl, cycloalkyl, aryl or heteroaryl], n=0, and R² is alkyl orcycloalkyl, then R¹ is not aryl, heteroaryl or alkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³ orNMeR³ [wherein R³ is (C₁₋₄)alkyl], n=0, and R² is (C₁₋₄)alkyl, then R¹is not phenyl bearing an N-substituted sulfonamido group;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, cycloalkyl, aryl or heterocycle, n=0, and R² isalkyl or cycloalkyl, then R¹ is not 3,4-dialkoxyphenyl,3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is H, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl orbenzyl, n=0, and R² is alkyl, cycloalkyl or hydroxyalkyl, then R¹is nottetrazolyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl,arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl,n=0, and R² is lower alkyl, then R¹ is not substituted phenyl orheteroaryl;

and with the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is H, alkyl, phenyl or benzyl, n=0, and R² is (C₁₋₄)alkyl,then R¹ is not phenyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=0, and R² is alkyl or hydroxyalkyl, then R¹is not fluoroalkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=0, and R² is alkyl, then R¹is not alkenyl or aryl;

and with the further proviso that if X is CH, Y is O, Z is NHR³ [whereinR³ is thiazolyl], n=1, and R² is (C₁₋₈)alkyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, phenyl or heteroaryl, then R¹is not phenyl,phenyl(C₂₋₄)alkenyl, heteroaryl, heterocycle, (C₁₋₈)alkyl,(C₂₋₆)alkenyl, or (C₃₋₇)cycloalkyl;

and with the further proviso that if X is CH, Y is O, Z is OH or NH₂,n=1, and R² is (C₁₋₅)alkyl, then R¹is not methyl or optionallyhalogenated phenyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂, n=0, andR² is n-Pr, then R¹ is not phenylethenyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂, n=0, andR² is alkyl, then R¹is not substituted phenyl or naphthyl;

and with the further proviso that if X is CH, Y is O, Z is NH₂ or NHR³wherein R³ is (C₁₋₄)alkyl, benzyl or p-fluorophenylmethyl, n=0, and R²is (C₁₋₄)alkyl, then R¹is not phenyl substituted with acylamino.

In a second aspect, the invention provides an inhibitor of NS5B havingthe formula I, or Ia, without the provisos.

In a third aspect, the invention provides an inhibitor of HCVreplication having the formula I, or Ia, without the provisos.

In a fourth aspect, the invention provides a method of treating orpreventing HCV infection in a mammal, comprising administering to themammal an effective amount of a compound of formula I, or Ia, withoutthe provisos.

In a fifth aspect, the invention provides a pharmaceutical compositionfor the treatment or prevention of HCV infection, comprising aneffective amount of a compound of formula I, or Ia, without theprovisos, and a pharmaceutically acceptable carrier.

In a sixth aspect, the invention provides a use for the manufacture of amedicament of formula I, or Ia, without the provisos, for the treatmentof HCV infection.

In a seventh aspect, the invention provides a use of a compound offormula I, or Ia, without the provisos, as an inhibitor of NS5B.

In an eighth aspect, the invention provides a use of a compound offormula I, or Ia, without the provisos, as an inhibitor of HCVreplication.

In a ninth aspect, the invention provides a method of treating HCVinfection in a mammal, comprising giving instructions to a third partyto administer a compound of formula I, or Ia, without the provisos to asubject suffering from HCV infection.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus generally described the invention, reference will now bemade to the accompanying drawing, showing by way of illustration apreferred embodiment thereof, and in which:

FIG. 1 shows an amino acid sequence of full length NS5B (SEQ ID NO 1) ofHCV.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions apply unless otherwise noted:

As used herein, the term “detectable derivative” is intended to refer tosubstituents, which “label” compounds of the present invention such thatwhen the compound is associated with the polymerase target, the presenceof the compound can be detected, measured and quantified. Examples ofsuch “labels” are intended to include, but are not limited to,fluorescent labels, calorimetric labels, and radioactive isotopes.

As used herein, the terms “(C₁₋₃)alkyl”, “(C₁₋₄)alkyl” or “(C₁₋₆)alkyl”,either alone or in combination with another radical, are intended tomean acyclic straight chain alkyl radicals containing up to three, fourand six carbon atoms respectively. Examples of such radicals includemethyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl.

As used herein, the term “(C₂₋₄) alkenyl”, either alone or incombination with another radical, is intended to mean an unsaturated,acyclic straight chain radical containing two to four carbon atoms.

As used herein. the term “(C₃₋₇)acycloalkyl”, either alone or incombination with another radical, means a cycloalkyl radical containingfrom three to seven carbon atoms and includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “aryl”, either alone or in combination withanother radical means aromatic radical containing six, or nine or tencarbon atoms, for example phenyl.

As used herein, the term “heterocycle” or “Het”, either alone or incombination with another radical, means a monovalent radical derived byremoval of a hydrogen from a five-, six-, or seven-membered saturated orunsaturated (including aromatic) heterocycle containing from one to fourheteroatoms selected from nitrogen, oxygen and sulfur. Furthermore,“heterobicyclic” as used herein, means a heterocycle as defined abovefused to one or more other cycle, be it a heterocycle or any othercycle. Examples of such heterocycles include, but are not limited to,pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene,diazepine, 1 H-imidazole, isoxazole, thiazole, tetrazole, piperidine,1,4-dioxane, 4-morpholine, pyridine, pyridine-N-oxide, pyrimidine,thiazolo[4,5-b]-pyridine, quinoline, or indole, or the followingheterocycles:

As used herein, the term “halo” means a halogen atom and includesfluorine, chlorine, bromine and iodine.

As used herein, the term “pharmaceutically acceptable salt” includesthose derived from pharmaceutically acceptable bases and is non-toxic.Examples of suitable bases include choline, ethanolamine andethylenediamine. Na⁺, K⁺, and Ca⁺⁺ salts are also contemplated to bewithin the scope of the invention (also see Pharmaceutical salts, Birge,S. M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein byreference).

Preferred Embodiments

Compounds of the invention act as inhibitors of NS5B RNA dependent RNApolymerase -type activity in vitro and in HCV infected individuals.

According to the first embodiment of this invention preferably compoundsof the invention have the following formula:

Preferably A is N or CR⁵, wherein R⁵ is H or (C₁₋₆ alkyl). Morepreferably A is N, CCH₃, or CH. Most preferably A is CH.

Preferably R⁶ is H or (C₁₋₆)alkyl. More preferably R⁶ is CH₃ or H. Mostpreferably R⁶ is H.

Preferably Z is NHR³, OR³ or OH. Most preferably Z is NHR³.

Alternatively preferably, compounds of the invention have the followingformulae:

With respect to compounds of formula (I), (Ia), (Ib), (Ic), and (Id),preferably R¹ is selected from the group consisting of 5- or 6-memberedheterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl,phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₁₋₆)alkyl, CF₃, 9- or 10-membered heterobicycle having 1 to 4heteroatoms selected from O, N and S,

wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrole, pyrrolidinyl, carboxy(C₂₋₄)alkenyl,phenoxy, —NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4,SO₃H, and NO₂.

More preferably R¹ is furyl, tetrahydrofuranyl, pyridyl,N-methylpyrrolyl, pyrrolyl, pyrazine, imidazole, isoquinoline, thiazole,pyrimidine, thiadiazole, pyrazole, isoxazole, indole, thiophenyl,1,3-benzodioxazole, 1,4-benzodioxan, CF₃, phenyl;

wherein said furanyl, tetrahydrofuranyl, pyridyl, N-methylpyrrolyl,pyrrolyl, pyrazine, isoquinoline, thiazole, pyrimidine, pyrazole,isoxazole, indole, thiophenyl, 1,3-benzodioxazole, 1,4-benzodioxan orphenyl being optionally substituted with from 1 to 4 substituentsselected from: (C₁₋₆alkyl), (C₁₋₄)alkoxy, —OCH₂CONH(CH₂)₂ ₃N(CH₃)₂,COOH, OH, halogen, CF₃, cyano, phenoxy, pyrrolidinyl, —NH(C₂₋₄)acyl,—O(CH₂)₂OH, NO₂, SO₃H,

Even more preferably R¹ is furanyl, pyridinyl, phenyl, pyridyl,thiophene, thiadiazole, 1,3-benzodioxazole, pyrazine, imidazole,pyrazole, isoxazole,

wherein said furan, pyridinyl, phenyl, thiophenyl, thiadiazole,1,3-benzodioxazole, pyrazine, imidazole, pyrazole, isoxazole beingoptionally substituted with from 1 to 4 substituents selected from:(C₁₋₆alkyl), halogen, CF₃, OH, —O(CH₂)₂OH,

Most preferably R¹ is furanyl, pyridinyl, thiophenyl and phenyl. Withrespect to compounds of formula (I), (Ia), (Ib), (Ic), and (Id),preferably R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, adamantyl, phenyl, andpyridyl, all of which is optionally substituted with from1 to 4substituents selected from:

halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl and OH.

More preferably R² is (C₁₋₆ alkyl), norbornane, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl,

Most preferably R² is cyclohexyl or cyclopentyl.

With respect to compounds of formula (I), (Ia), (Ib), (Ic), and (Id),preferably R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S;

wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are alloptionally substituted with from 1 to 4 substituents selected from:

OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₁₋₆)alkyl-hydroxy, phenyl,benzyloxy, halogen, (C₂₋₄)alkenyl, (C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, andcarboxy(C₂₋₄)alkenyl, 5- or 6-membered heterocycle having 1 to 4heteroatoms selected from O, N and S, said heterocycle being optionallysubstituted with from 1 to 4 substituents selected from:

(C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH, NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆ alkyl)₂, wherein p is an integerfrom 1 to 4;

9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected fromO, N and S, said heterobicycle being optionally substituted with from 1to 4 substituents selected from:

halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, nitro, —CONH₂, —COCH₃,(C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, OH, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, triazolyl, (C₁₋₄)alkoxy,cyano, azido, —O-(C₁₋₆)alkyl COOH, —O-(C₁₋₆)alkyl COO-(C₁₋₆)alkyl,—NHCOCOOH, —NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃;

6- or 10-membered aryl being optionally substituted with from 1 to 4substituents selected from:

halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, nitro, —CONH₂, —COCH₃,(C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH,NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano,azido, —O-(C₁₋₆)alkyl COOH, —O-(C₁₋₆)alkyl COO-(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃;

coumarin, (C₁₋₆)alkyl-amino, di-(C₁₋₆)alkyl-amino, C(halogen)₃,—NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl, —CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH,—CO—NH-alanyl, —(CH₂)_(p)COOH, —OCH₂Ph, —CONHbenzyl, —CONHpyridyl,—CONHCH₂pyridyl, —CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄)alkyl-morpholino, —CONH(C₂₋₄) alkyl-pyrrolidino, —CONH(C₂₋₄)alkyl-N-methylpyrrolidino, —CONH(C₂₋₄) alkyl-(COOH)-imidazole,—CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH, —CONH(C₆₋₁₀) aryl-COOH,—CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆) alkyl-COO(C₁₋₆) alkyl,—CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from;

COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH;

—CONH(C₆₋₁₀) aryl-5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N and S, said heterocycle being optionally substitutedwith from 1 to 4 substituents selected from:

COOH and (CH₂)_(p)COOH;

—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from:

COOH and (CH₂)_(p)COOH; and

—O(CH₂)_(p)tetrazolyl;

wherein p is an integer from 1 to 4.

More preferably, R³ is

wherein preferably R^(3a) is selected from H, 5- to 10-atom heterocyclehaving 1 to 4 heteroatoms selected from O, N and S; COOH,COO(C₁₋₆)alkyl, said heterocycle being optionally substituted with from1 to 4 substituents selected from the group consisting of: CH₃, CF₃, OH,CH₂COOH, COOH, NHCH(CH₃)₂, NHCOCH₃, NH₂, NHCH₃, and N(CH₃)₂, —CONH₂,—COCH₃ —(CH₂)_(p)COOH, —OCH₂Ph, —CH₂—(C₆₋₁₀)aryl-COOH, —CONHpyridyl,—CONHCH₂pyridyl, —CONH(C₂₋₄)alkylN(CH₃)₂.

Most preferably R^(3a) is COOR^(3g), CONHR^(3f), or

wherein preferably R^(3e) is H, (C₁₋₆ alkyl), amino, NH(C₁₋₆ alkyl),N{(C₁₋₆ alkyl)}₂, or NHCO(C₁₋₆ alkyl).

Preferably R^(3f) is H, —(C₂₋₄) alkyl-morpholino, —(C₂₋₄)alkyl-pyrrolidino, —(C₂₋₄) alkyl-N-methylpyrrolidino; (C₁₋₆alkyl)N(CH₃)₂, (C₁₋₆ alkyl)OH, CH(CH₂OH)₂ or CH₂C(OH)CH₂OH.

Most preferably R^(3f) is H

Preferably R^(3g) is H or (C₁₋₆ alkyl). More preferably R^(3g) is H orCH₃.

Preferably R^(3b) is selected from H, OH, amino, 5- to 10-atomheterocycle having 1 to 4 heteroatoms selected from O, N and S; saidheterocycle being optionally substituted with OH, COOH, CH₃, CF₃,CH₂COOH, —O(C₁₋₃)alkylCOOH, —NHCOCOOH, —NHSO₂CH₃, —NHSO₂CF₃,

Most preferably R^(3b) is OCH₂COOH or OH.

Preferably R^(3c) is selected from H, (C₁₋₆)alkyl or —(CH₂)_(p)COOH,wherein p is an integer from 1 to 4. More preferably R^(3c) is H, CH₃ or—CH₂COOH.

Preferably R^(3d) is H or (C₁₋₆ alkyl). More preferably R^(3d) is H orCH₃. Most preferably R^(3d) is H.

Alternatively more preferably, R³is:

wherein R^(3a) is as defined above.

Preferably R^(3j) is (C₁₋₄)alkoxy, OH, O(C₁₋₆ alkyl)COOH, (C₁₋₆ alkyl),halogen; (C₂₋₆)alkenylCOOH, (C₁₋₆)alkyl-hydroxy, COOH, or azido.

Preferably R^(3k) is OH, (CH₂)_(p)COOH where p is an integer from 1 to4, amino, (C₁₋₄)alkoxy, NHCOCOOH, NH(C₁₋₆ alkyl)COOH, O(C₁₋₆ alkyl)COOH,COOH, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selectedfrom O, N and S, said heterocycle being optionally substituted with from1 to 4 substituents selected from the group consisting of:

CH₃, CF₃, OH, CH₂COOH, COOH; —O-(C₁₋₆)alkyl COOH,

 NHCONH₂, NHCN, NHCHO, NHSO₂CF₃, NHCOCH₃, NHSO₂CH₃, CONH₂,(C₃₋₆)cycloalkylCOOH, (C₂₋₆)alkenylCOOH, and NHCOCH(OH)COOH.

Preferably R³¹ is O(C₁₋₆ alkyl)COOH, (C₁₋₆ alkyl), or halogen.

Preferably m is an integer from 0 to 4. Most preferably m is 1.

Alternatively even more preferably, R³ is:

wherein R^(3k) is as defined above.

Preferably R^(3m) is H or OH.

Preferably R^(3p) is H, halogen, or (C₁₋₆alkyl).

Preferably R^(3r) is H, halogen, or (C₁₋₆ alkyl).

Alternatively more preferably, R³ is

Preferably R^(3o) is OH or O(C₁₋₆ alkyl)COOH.

Alternatively more preferably, R³ is:

wherein R^(3a) is as defined above.

Preferably J is S or N(C₁₋₆ alkyl). More preferably J is S or N(CH₃)

Preferably R^(3n) is H or amino.

Alternatively even more preferably, compounds of the invention have thefollowing formula:

wherein R¹, R² and R^(3b) are as defined above.

Alternatively even more preferably, compounds of the invention have thefollowing formula:

wherein R¹, R², R^(3b), and R^(3c) are as defined above.

Alternatively even more preferably, compounds of the invention have thefollowing formula:

wherein R¹, R², R^(3j), and R^(3k) are as defined above.

According to a second aspect of the invention, the compounds of formula(Ib), (Ic), and (Id), or pharmaceutically acceptable salts thereof, areeffective as inhibitors of RNA dependent RNA polymerase activity of theenzyme NS5B, encoded by HCV.

According to a third aspect of the invention, the compounds of formula(Ib), (Ic), and (Id), or pharmaceutically acceptable salt thereof, areeffective as inhibitors of HCV replication.

According to a fourth aspect of the invention, there is provided amethod of treating or preventing HCV infection in a mammal, comprisingadministering to the mammal an effective amount of the compounds offormula (Ib), (Ic), and (Id), or pharmaceutically acceptable saltsthereof.

According to a fifth aspect of the invention, there is provided apharmaceutical composition for the treatment or prevention of HCVinfection, comprising an effective amount of a compound of formula (Ib),(Ic) or (Id), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

According to a sixth aspect of the invention, there is provided a usefor the manufacture of a medicament of formula (Ib), (Ic), and (Id), forthe treatment of HCV infection.

According to a seventh aspect of the invention, there is provided a useof a compound of formula (Ib), (Ic), and (Id), as an inhibitor of NS5B.

According to an eighth aspect of the invention, there is provided a useof the compounds of formula (Ib), (Ic), and (Id), as an inhibitor of HCVreplication.

According to a ninth aspect of the invention, there is provided a methodof treating HCV infection in a mammal, comprising giving instructions toa third party to administer a compound of formula (Ib), (Ic), and (Id),to a subject suffering from HCV infection.

Specific Embodiments

Included within the scope of this invention are all compounds of formula(I), (Ia), (Ib), (Ic), or (Id), as presented in Tables 1 to 22.

Anti-NS5B Activity

The ability of the compounds of formula (I) to inhibit RNA synthesis bythe RNA dependent RNA polymerase of HCV, NS5B, can be demonstrated byany assay capable of measuring RNA dependent RNA polymerase activity. Asuitable assay is described in the examples.

Specificity for RNA Dependent RNA Polymerase Activity

To demonstrate that the compounds of the invention act by specificinhibition of NS5B, the compounds may be tested for the lack ofinhibitory activity in other RNA dependent RNA polymerase assays or DNAdependant RNA polymerase assays.

When a compound of formula (I), or one of its therapeutically acceptablesalts, is employed as an antiviral agent, it is administered orally,topically or systemically to mammals, e.g. humans, rabbits or mice, in avehicle comprising one or more pharmaceutically acceptable carriers, theproportion of which is determined by the solubility and chemical natureof the compound, chosen route of administration and standard biologicalpractice.

For oral administration, the compound or a therapeutically acceptablesalt thereof can be formulated in unit dosage forms such as capsules ortablets each containing a predetermined amount of the active ingredient,ranging from about 25 to 500 mg, in a pharmaceutically acceptablecarrier.

For topical administration, the compound can be formulated inpharmaceutically accepted vehicles containing 0.1 to 5 percent,preferably 0.5 to 5 percent, of the active agent. Such formulations canbe in the form of a solution, cream or lotion.

For parenteral administration, the compound of formula (I) isadministered by either intravenous, subcutaneous or intramuscularinjection, in compositions with pharmaceutically acceptable vehicles orcarriers. For administration by injection, it is preferred to use thecompounds in solution in a sterile aqueous vehicle which may alsocontain other solutes such as buffers or preservatives as well assufficient quantities of pharmaceutically acceptable salts or of glucoseto make the solution isotonic.

Suitable vehicles or carriers for the above noted formulations aredescribed in pharmaceutical texts, e.g. in “Remington's The Science andPractice of Pharmacy”, 19th ed., Mack Publishing Company, Easton, Pa.,1995, or in “Pharmaceutical Dosage Forms And Drugs Delivery Systems”,6th ed., H. C. Ansel et al., Eds., Williams & Wilkins, Baltimore, Md.,1995.

The dosage of the compound will vary with the form of administration andthe particular active agent chosen. Furthermore, it will vary with theparticular host under treatment. Generally, treatment is initiated withsmall increments until the optimum effect under the circumstance isreached. In general, the compound of formula I is most desirablyadministered at a concentration level that will generally affordantivirally effective results without causing any harmful or deleteriousside effects.

For oral administration, the compound or a therapeutically acceptablesalt is administered in the range of 10 to 200 mg per kilogram of bodyweight per day, with a preferred range of 25 to 150 mg per kilogram.

For systemic administration, the compound of formula (I) is administeredat a dosage of 10 mg to 150 mg per kilogram of body weight per day,although the aforementioned variations will occur. A dosage level thatis in the range of from about 10 mg to 100 mg per kilogram of bodyweight per day is most desirably employed in order to achieve effectiveresults.

Although the formulations disclosed hereinabove are indicated to beeffective and relatively safe medications for treating HCV infections,the possible concurrent administration of these formulations with otherantiviral medications or agents to obtain beneficial results alsoincluded. Such other antiviral medications or agents include interferonor interferon and ribavirin.

Methodology and Synthesis

Benzimidazole derivatives or analogs according to the present inventioncan be prepared from known starting materials by following Scheme 1,shown below wherein R¹, R² and R³ are as previously described.

In carrying out the route illustrated in Scheme 1, illustrated above, asuitably protected form of 4-chloro-3-nitrobenzoic acid or4-fluoro-3-nitrobenzoic acid is reacted with a primary amine R²NH₂.Amines are of commercial sources or can be prepared by literaturemethods. This reaction is carried out in a suitable solvent such asDMSO, DMF or the like, at temperatures ranging from 20° C. to 170° C.,or alternatively without solvent by heating the two components together.The nitro group of these derivatives is subsequently reduced to thecorresponding aniline, using a reducing agent such as hydrogen gas inthe presence of a catalyst (e.g. Pd metal and the like), metals in thepresence of mineral acids (e.g. Fe or Zn with aqueous HCl), or metalsalts (SnCl₂). The diamino derivatives that are obtained are condensedwith commercially available aldehydes R¹CHO in the presence of anoxidizing agent (e.g. air, oxygen, iodine, oxone®, quinones, peroxidesetc.) to give benzimidazole 5-carboxylates.

Alternatively, other methods for benzimidazole ring construction can beemployed, such as condensation of the diamino derivatives withcarboxylic acids, nitrites or amides, in the presence or absence of acatalyst. Such methods are well known in the literature to those skilledin the art. Saponification of the ester protecting group of suchderivatives using alkali metal hydroxides, followed by neutralizationwith weak acids (e.g. AcOH) generates free 5-carboxybenzimidazolederivatives of general formula I (X=CH, Y=O, Z=OH, n=0).

Derivatives of formula I in which Z=NHR³ may be obtained by condensationof 5-carboxybenzimidazoles of formula I (X=CH or N, Y =O, Z =0H) withamines H₂NR³ through formation of an amide bond. Amines H₂NR³ are fromcommercial sources or can be prepared following literature procedures.Condensation of the carboxylic acid with amine H₂NR³ can be accomplishedusing standard peptide bond forming reagents such as TBTU, BOP, EDAC,DCC, isobutyl chloroformate and the like, or by activation of thecarboxyl group by conversion to the corresponding acid chloride prior tocondensation with an amine. This coupling reaction can then be followedby elaboration of functional groups present in R³ and protecting groupsare subsequently removed in the last stage of the synthesis, ifnecessary, to provide compounds of formula I.

Alternatively, benzimidazole derivatives or analogs according to thepresent invention can be prepared on a solid support as described inScheme 2, below, wherein R¹, R² and R³ are as previously described.

In carrying out the synthetic route illustrated in Scheme 2,4-fluoro-3-nitrobenzoic acid is converted to the acid chloridederivative using standard procedures (e.g. thionyl chloride, oxalylchloride, phosgene and the like in the presence of a catalytic amount ofDMF) in an inert solvent such as CH₂Cl₂.

Wang resin is esterified with this acid chloride by condensation in thepresence of an organic tertiary amine such as triethylamine,N-methylmorpholine, DIEA and the like. Other types of resins are wellknown to those skilled in the art, for example Rink resin, which may befunctionalized without deviating from the scope of the invention. Thefunctionalised resin thus obtained is then elaborated to resin-boundbenzimidazole carboxylate derivatives as described above for thesolution-phase chemistry. Cleavage of the benzimidazole from the resinis carried out with strong acids (e.g. trifluoroacetic acid) to givebenzimidazole 5-carboxylic acids of general formula I (X=CH or N, Y=O,Z=OH, n=0), within the scope of this invention. As described previouslyin solution phase, carboxylic acids of general formula I (X=CH or N,Y=O, Z=OH) can be elaborated to benzimidazole derivatives of generalformula I (Z=NHR³) by condensation with amines R³NH₂.

EXAMPLES

The present invention is illustrated in further detail by the followingnon-limiting examples. All reactions were performed in a nitrogen orargon atmosphere. Temperatures are given in degrees Celsius. Solutionpercentages or ratios express a volume to volume relationship, unlessstated otherwise. Mass spectral analyses were recorded usingelectrospray mass spectrometry. Abbreviations or symbols used hereininclude:

DIEA: diisopropylethylamine;

DMAP: 4-(dimethylamino)pyridine;

DMSO: dimethylsulfoxide;

DMF: N,N-dimethylformamide;

Et: ethyl;

EtOAc: ethyl acetate;

Et₂O: diethyl ether;

HPLC: high performance liquid chromatography;

Pr: isopropyl

Me: methyl;

MeOH: Methanol;

MeCN: acetonitrile;

Ph: phenyl;

TBE: tris-borate-EDTA;

TBTU: 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

MS (ES): electrospray mass spectrometry;

PFU: plaque forming units;

DEPC: diethyl pyrocarbonate;

DTT: dithiothreitol

EDTA: ethylenediaminetetraacetate

HATU: O-(7-azabenzotriazol-1 -yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate

EDAC: see ECD

DCC: 1,3-Dicyclohexyl carbodiimide

HOBt: 1-Hydroxybenzotriazole

ES⁺: electro spray (positive ionization)

ES: electro spray (negative ionization)

DCM: dichloromethane

TBME: tert-butylmethyl ether

TLC: thin layer chromatography

AcOH: acetic acid

EtOH: ethanol

DBU: 1,8-diazabicyclo[5.4.0]under-7-ene

BOC: tert-butyloxycarbonyl

Cbz: carbobenzyloxy carbonyl

BINAP: 2,2′-Bis(diphenylphosphine)-1, 1 -binaphthyl

^(i)PrOH: isopropanol

NMP: N-methylpyrrolidone

EDC: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride

RNAsin: A ribonuclease inhibitor marketed by Promega Corporation

Tris: 2-amino-2-hydroxymethyl-1,3-propanediol

UMP: uridine 5′-monophosphate

UTP: uridine 5′-triphosphate

Examples 1-158 Illustrate Methods of Synthesis of RepresentativeCompounds of this Invention Example 1 (Entry 7021, Table 7)1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid

4-Chloro-3-nitrobenzoic acid, ethyl ester

4-Chloro-3-nitrobenzoic acid (100.0 g, 0.496 mole) was suspended inethanol (250 mL) and thionyl chloride (54 mL, 0.74 mole) was addeddrop-wise over 15 min. The mixture was then reflux for 2 h. Aftercooling to ambient temperature, volatiles were removed under reducedpressure and the residue was co-evaporated twice with ethanol (2×250mL). The residue was crystallized from hot ethanol to give the desiredethyl ester as light yellow needles (109.8 g, 96% yield).

4-Cyclohexylamino-3-nitrobenzoic acid ethyl ester

Ethyl 4-chloro-3-nitrobenzoate (20.00 g, 87 mmol) was dissolved in DMSO(50 mL) and cyclohexylamine (2.1 equiv. 21 mL, 183 mmol) was added andthe mixture stirred at 60° C. for 5 h. After cooling to ambienttemperature, the reaction mixture was added drop-wise with vigorousstirring to water (500 mL). After stirring for an additional 15 min, theprecipitated solid was collected by filtration, washed with water anddried. The title compound (25.67 g, 100% yield) was obtained as a brightyellow solid.

3-Amino-4-cyclohexylamino benzoic acid ethyl ester

The nitro derivative from above (24.28 g, 83 mmol) was hydrogenated (1atm H₂) over 20% Pd(OH)₂ on carbon (200 mg) in MeOH (150 mL) for 3 days.The catalyst was removed by filtration and volatiles removed underreduced pressure to give the title diamine (21.72 g, 100% yield) as adark purple solid.

1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid

The diamine from above (3.20 g, 12.2 mmol) was dissolved in DMF (15 mL)and water (0.5 mL). 2-Pyridine carboxaldehyde (1.45 mL, 15 mmol) wasadded followed by oxone® (0.65 equivalent, 8 mmol, 4.92 g). The mixturewas stirred 1 h at room temperature. Water (60 mL) was added, and the pHof the reaction mixture was brought up to 9 by addition of 1 N NaOH. Thebrown precipitate that formed was collected by filtration, washed withwater and dried. The crude benzimidazole ethyl ester was obtained in 80%yield (3.43 g).

The ester from above (2.36 g, 7.53 mmol) was dissolved in MeOH (15 mL)and 2 N NaOH (20 mmol, 10 mL) was added. The mixture was stirred at 60°C. for 2 h and then cooled to room temperature. MeOH was removed underreduced pressure and the residue acidified to pH 4 with glacial AcOH.The precipitated carboxylic acid was collected by filtration, washedwith water and dried to give the free acid as a beige solid (2.20 g, 91%yield).

Example 2 (Entry 7018, Table 7)1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid

Ethyl 3-amino-4-(aminocyclohexyl)benzoate (3.67 g, 13.99 mmol) wasdissolved in DMF (10 mL) and water (1 mL). Oxone® (9. 8 mmol, 6.02 g)was added followed by 3-furaldehyde (1.44 g, 15 mmol). The mixture wasstirred 45 min at room temperature. 4 N NaOH (20 mL) was added and themixture stirred at 60° C. for 18 h. After cooling to room temperature,water (100 mL) was added and insoluble impurities removed by filtrationthrough celite. AcOH was then added to precipitate the product as abeige solid. The precipitated carboxylic acid was collected byfiltration, washed with water and dried to give the title compound as abeige solid (3.69 g, 85% yield).

Example 3 (Entry 2108, Table 2)1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid[2-(3,4-dimethoxyphenyl)ethyl]amide

1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid (0.060g, 0.19 mmol), 3,4-dimethoxyphenethylamine (35 μL, 0.21 mmol) and TBTU(0.090 g, 0.28 mmol) were dissolved in DMF (1 mL), and DIEA (330 μL, 1.9mmol) was added. The mixture was stirred 1 h at room temperature, whenHPLC analysis indicated completion of the coupling reaction. Thereaction mixture was added drop-wise with vigorous stirring to 1 N NaOH(10 mL). The precipitated product was collected by filtration, washedwith water and dried. The title amide derivative was obtained as a graysolid (0.056 g, 60% yield, 98% homogeneity by HPLC).

Example 4 General Procedure for the Preparation of Racemiα-alkylbenzylamine Derivatives

According to the general scheme shown above, and adapting the procedureof D. J. Hart et al. (J. Org. Chem. 1983, 48, 289), aromatic aldehydesare reacted first with lithium bis(trimethylsilyl)amide and then with aGrignard reagent in a suitable solvent such as Et₂O, tetrahydrofuran,toluene and the like, at temperatures ranging from 0° C. to 120° C.Following hydrolysis, the desired racemic α-alkylbenzylamines wereisolated after conversion to their hydrochlorides. In this manner, avariety of racemic α-alkylbenzylamines were synthesized withsubstitution as previously described in this invention:

Dl-3,4-Dimethoxy-α-methylbenzylamine hydrochloride

3,4-Dimethoxybenzaldehyde (5.00 g, 30 mmol) was dissolved in anhydrousTHF (10 mL) and the solution cooled in ice under an argon atmosphere.Lithium bis(trimethylsilyl)amide (1 M in THF, 36 mmol, 36 mL) was addeddrop-wise and the resulting mixture stirred at 0° C. for 30 min.Methylmagnesium bromide (1.4 M in THF, 2 equiv., 72 mmol, 43 mL) wasadded and the solution allowed to warm up to room temperature. It wasthen reflux for 24 h. The reaction mixture was then cooled to roomtemperature and poured into saturated aqueous NH₄Cl (200 mL). Themixture was extracted twice with DCM (75 mL) and the extract dried overMgSO₄. The solution was concentrated to a volume of about 25 mL underreduced pressure and diluted with an equal volume of Et₂O. Excesshydrogen chloride (4 M in dioxane) was added, and the resultingprecipitate collected by filtration. It was washed with Et₂O and driedin vacuo. DL-3,4-Dimethoxy-α-methylbenzylamine hydrochloride (5.1 g, 78%yield) was obtained as an orange solid.

Dl-3,4-Dimethoxy-α-ethylbenzylamine hydrochloride

Following the general procedure, starting from 3,4-dimethoxybenzaldehydeand ethylmagnesium bromide, after a reaction time of 48 h, the titlecompound was obtained as a cream colored solid in 70% yield.

Dl-3,4-Dimethoxy-α-isobutylbenzylamine hydrochloride

Following the general procedure, starting from 3,4-dimethoxybenzaldehydeand isobutylmagnesium bromide, after a reaction time of 48 h, the titlecompound was obtained as a pink solid in 81% yield.

Dl-3,4-Dimethoxy-α-(2-propenyl)benzylamine hydrochloride

Following the general procedure, starting from 3,4-dimethoxybenzaldehydeand allylmagnesium bromide, after a reaction time of 48 h, the titlecompound was obtained as a cream colored solid in 89% yield.

Dl-3,4-Dimethoxy-α-isopropylbenzylamine hydrochloride

Following the general procedure, starting from 3,4-dimethoxybenzaldehydeand isopropylmagnesium chloride, after a reaction time of 72 h, thetitle compound was obtained as a cream colored solid in 75% yield.

DL-3,4-Dimethoxy-α-tert-butyl-benzylamine hydrochloride

Following the general procedure, starting from 3,4-dimethoxybenzaldehydeand tert-butylmagnesium chloride, after a reaction time of 72 h, thetitle compound was obtained as a cream colored solid in quantitativeyield.

DL-4-Methoxy-3-methyl-α-methylbenzylamine hydrochloride

Following the general procedure, starting from3-methyl-para-anisaldehyde and methylmagnesium bromide, after a reactiontime of 48 h, the title compound was obtained as a cream colored solidin quantitative yield.

DL-4-Ethoxy-3-methoxy-α-methylbenzylamine hydrochloride

Following the general procedure, starting from4-ethoxy-meta-anisaldehyde and methylmagnesium bromide, after a reactiontime of 72 h, the title compound was obtained as a pink solid in 86%yield.

DL-3-Ethoxy-4-methoxy-α-methylbenzylamine hydrochloride

Following the general procedure, starting from3-ethoxy-para-anisaldehyde and methylmagnesium bromide, after a reactiontime of 96 h, the title compound was obtained as a light brown solid in82% yield.

DL-3,4-Diethoxy-α-methylbenzylamine hydrochloride

Following the general procedure, starting from 3,4-diethoxybenzaldehydeand methylmagnesium bromide, after a reaction time of 96 h, the titlecompound was obtained as a pink solid in 75% yield.

Example 5 (Entry 2042Table 2)1-Cyclohexyl-2-pyridin-2-yl-1h-benzoimidazole-5-carboxylic acid[(R)-1-(3,4-dimethoxyphenyl)ethyl]amide

3′,4′-Dimethoxyphenylacetyl chloride

3′,4′-Dimethoxyphenylacetic acid (10.00 g, 51 mmol) was dissolved in DCM(100 mL) and DMF (100 μL) was added. Oxalyl chloride (1.05 equiv., 53.5mmol, 4.67 mL) was added drop-wise and the mixture stirred at roomtemperature until gas evolutions ceased. The solution was then refluxedfor 30 min, cooled to room temperature and concentrated under reducedpressure. The crude acid chloride was used directly in the next step.

(R)-3-[2-(3,4-Dimethoxyphenyl)-ethanoyl]4-isopropyl-oxazolidin-2-one

(R)-4-Isopropyl-2-oxazolidinone (6.59 g, 51 mmol) was dissolved inanhydrous THF (95 mL) under an argon atmosphere. The solution was cooledto −50° C. and n-BuLi (2.3 M in hexane, 51 mmol, 22 mL) was addeddrop-wise. The resulting white suspension was stirred for 30 min at −40°C. and then cooled further to −78° C. The acid chloride from above (51mmol) in THF (10 mL +5 mL rinse) was added drop-wise over 5 min and themixture stirred for 30 min at −78° C. The reaction mixture was thenallowed to warm to 0° C. and stirred an additional 1 h at thattemperature. After quenching with saturated aqueous NH₄Cl (25 mL), THFwas removed under reduced pressure, water (25 mL) was added and theproduct extracted with EtOAc (150 mL). The extract was washed with 5%aqueous NaHCO₃ (2×50 mL) and brine (50 mL), and dried over MgSO₄.Volatiles were removed under reduced pressure, and the residue purifiedby flash chromatography on silica gel using 40% EtOAc in hexane aseluent (11.06 g, 70% yield).

(R)-3-[2-(3,4-Dimethoxyphenyl)-propanoyl]-4-isopropyl-oxazolidin-2-one

The oxazolidinone from above (5.24 g, 17 mmol) was dissolved inanhydrous THF (75 mL) and the solution cooled to −78° C. under an argonatmosphere. Lithium bis(trimethylsilyl)amide (1 M in THF, 1.15 equiv.,19.6 mmol, 19.6 mL) was added drop-wise and the mixture stirred 30 minat −78° C. Iodomethane (17 mmol, 1.06 mL) was added and the reactionmixture stirred 1 h at −78 ° C. and then at room temperature for 2 h.After quenching with 1 M KHSO₄ (25 mL), THF was removed under reducedpressure and the product extracted with EtOAc (150 mL). The extract waswashed successively with 1 M KHSO₄ (25 mL), 10% aqueous NaHCO₃ (2×25 mL)and brine (25 mL). After drying (MgSO₄) and removal of volatiles underreduced pressure, the crude product was purified by flash chromatographyon silica gel using 30% EtOAc in hexane as eluent to give the titlecompound as a white solid (2.93 g, 53% yield). ¹H NMR analysis indicatesa 9:1 mixture of diastereomers in favor of the desired (R,R)-isomer.

(R)-2-(3,4-Dimethoxyphenyl)propionic acid

The oxazolidinone from above (2.72 g, 8.5 mmol) was dissolved in THF (40mL) and water (15 mL) was added, followed by 30% hydrogen peroxide (4.36mL, 42 mmol) and LiOH monohydrate (0.426 g, 10.2 mmol). The mixture wasstirred for 1 h. THF was removed under reduced pressure and saturatedaqueous NaHCO₃ (10 mL) was added. The solution was washed with DCM (2×25mL) and then acidified to pH 1 with 6 NHCl. The product was extractedwith EtOAc (2×50 mL) and the extract dried over MgSO₄. After evaporationof the solvent, the crude title compound (1.855 g) was obtained as aclear oil.

[(R)-1-(3,4-Dimethoxyphenyl)-ethyl]-carbamic acid tert-butyl ester

(R)-3′,4′-Dimethoxy-2-methylphenylAcetic acid (1.505 g, 7.16 mmol) wasdissolved in toluene (20 mL). Diphenylphosphoryl azide (1.70 mL, 7.87mmol) and triethylamine (1.20 mL, 8.59 mmol) were added and the mixturestirred at room temperature for 20 min and then at 80° C. for 3h.tert-Butanol (5 equiv., 39.2 mmol, 3.75 mL) was added and the heating to80 ° C. continued for 20 h. The reaction mixture was then cooled to roomtemperature, diluted with Et₂O (100 mL) and washed successively with 1 MKHSO₄ (2×25 mL), saturated aqueous NaHCO₃ (2×25 mL) and brine (25 mL).After drying (MgSO₄), solvents were removed under reduced pressure andthe residue purified by flash chromatography on silica gel using 15-20%EtOAc in hexane as eluent. The title amine carbamate was obtained as awhite solid (0.72 g)

(R)-1-(3,4-Dimethoxyphenyl)-ethyl-ammonium chloride

(R)-N-tert-Butyloxycarbonyl-3′,4′-dimethoxy-α-methylbenzylamine fromabove (0.653 g, 2.3 mmol) was stirred for 1 h in 4 N hydrogenchloride-dioxane (4 mL). Volatiles were removed under reduced pressureto give the title amine hydrochloride as a white solid (0.518 g).

1-Cyclohexyl-2-pyridin-2-yl-1H-benzoimidazole-5-carboxylic acid[(R)-1-(3,4-dimethoxyphenyl)-ethyl]amide hydrochloride

The carboxylic acid of example 1 (0.075 g, 0.23 mmol), TBTU (1.5 equiv.,0.34 mmol, 0.111 g) and triethylamine (5 equiv., 1.15 mmol, 0.16 mL)were dissolved in DMF (0.5 mL) and the (R)-amine hydrochloride fromabove (0.051 g, 0.23 mmol) was added. The mixture was stirred for 1 h atroom temperature and quenched by addition of 1 N NaOH (5 mL) and water(10 mL). The gummy precipitate was extracted into EtOAc (75 mL), washedwith brine and dried (MgSO₄). The solvent was evaporated under reducedpressure and the residue dissolved in EtOAc (1 mL). TBME (10 mL) wasadded followed by hexane (10 mL). The precipitate that formed wascollected by filtration, washed with 1:1 TBME/hexane and dried. Theproduct was further purified by flash chromatography on silica gel usingEtOAc as eluent and then converted to its hydrochloride salt by reactionwith hydrogen chloride in ether. The title compound was obtained as awhite solid (0.065 g).

Example 6 General procedure for the Preparation of Racemic PhenylglycineMethyl Ester Hydrochloride Derivatives

Aromatic aldehydes, substituted according to the scope of the presentinvention, were reacted with an alkali metal cyanide (preferably sodiumor potassium cyanide) in a mixture of aqueous ammonium chloride andammonium hydroxide and a co-solvent such as MeOH or ethanol. Theaminonitriles formed were hydrolyzed to the corresponding racemicphenylglycines in boiling aqueous mineral acid (preferably hydrochloricacid), and then converted to the racemic phenylglycine methyl esterhydrochlorides by reaction with MeOH in the presence of either thionylchloride, oxalyl chloride, acetyl chloride, phosgene, hydrogen chlorideor the like.

Racemic Piperonylglycine Methyl Ester Hydrochloride

Piperonal (8.50 g, 56.6 mmol) was dissolved in MeOH (25 mL) and asolution of NaCN (2.77 g, 56.6 mmol) and ammonium chloride (3.33 g, 62mmol) in 30% aqueous ammonium hydroxide was added. After stirringovernight at room temperature, the supernatant was decanted from oilypolymeric residues and MeOH removed from the aqueous phase under reducedpressure. The aqueous phase was then extracted with EtOAc. Theaminonitrile present in the extract was then extracted into 6 NHCl (2×50mL), the aqueous acid phases combined and refluxed for 8 h. Water wasremoved under reduced pressure to precipitate out the phenylglycinederivative as the hydrochloride salt that was collected by filtrationand dried in vacuo (2.20 g).

The crude amino acid from above (1.00 g, 4.3 mmol) was dissolved in MeOH(10 mL) and thionyl chloride (1.5 equiv., 0.48 mL) was added drop-wise.The mixture was refluxed for 3 h, and then volatiles were removed underreduced pressure. The residue was co-evaporated 3 times with MeOH (25mL) and the residual solid triturated with Et₂O. The white solid wascollected and dried (0.98 g, 92% yield).

Racemic 3,4-dimethoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from3,4-dimethoxybenzaldehyde, the phenylglycine hydrochloride was obtainedin 29% yield, and the corresponding methyl ester hydrochloride in 96%yield.

Racemic 3,4,5-trimethoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from3,4,5-trimethoxybenzaldehyde, the phenylglycine hydrochloride wasobtained in 72% yield, and the corresponding methyl ester hydrochloridein 92% yield.

Racemic 4-methoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from 4-methoxybenzaldehyde,the phenylglycine hydrochloride was obtained in 25% yield, and thecorresponding methyl ester hydrochloride in 95% yield.

Racemic 3-methoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from 3-methoxybenzaldehyde,the phenylglycine hydrochloride was obtained in 43% yield, and thecorresponding methyl ester hydrochloride in 99% yield.

Racemic 2-methoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from 2-methoxybenzaldehyde,the phenylglycine hydrochloride was obtained in 11% yield, and thecorresponding methyl ester hydrochloride in 92% yield.

Racemic 3,4-diethoxyphenylglycine methyl ester hydrochloride

Following the general procedure and starting from3,4-diethoxybenzaldehyde, the phenylglycine hydrochloride was obtainedin 9% yield, and the corresponding methyl ester hydrochloride in 99%yield.

Racemic 3,4-dimethylphenylglycine methyl ester hydrochloride

Following the general procedure and starting from3,4-dimethylbenzaldehyde, the phenylglycine hydrochloride was obtainedin 56% yield, and the corresponding methyl ester hydrochloride in 97%yield.

Racemic 4-isopropylphenylglycine methyl ester hydrochloride

Following the general procedure and starting from4-isopropylbenzaldehyde, the phenylglycine hydrochloride was obtained in10% yield, and the corresponding methyl ester hydrochloride in 99%yield.

Racemic 4-trifluoromethylphenylglycine methyl ester hydrochloride

Following the general procedure and starting from4-trifluoromethylbenzaldehyde, the phenylglycine hydrochloride wasobtained in 53% yield, and the corresponding methyl ester hydrochloridein 78% yield.

Racemic 4-chlorophenylglycine methyl ester hydrochloride

Following the general procedure and starting from 4-chlorobenzaldehyde,the phenylglycine hydrochloride was obtained in 27% yield, and thecorresponding methyl ester hydrochloride in 83% yield.

Racemic 2-chlorophenylglycine methyl ester hydrochloride

Following the general procedure and starting from 2-chlorobenzaldehyde,the phenylglycine hydrochloride was obtained in 25% yield, and thecorresponding methyl ester hydrochloride in 93% yield.

Example 7 (Entry 16006, Table 16)(S)-{[1-(1-Cyclohexyl2-furan-3-yl-1H-benzoimidazole-5-yl)-methanoyl]-amino}-(3,4-dimethoxyphenyl)aceticacid:

(S)-3-[(S)-2-Azido-2-(3,4-dimethoxyphenyl)-ethanoyl]-4-isopropyl-oxazolidin-2-one

The (S)-N-acyloxazolidinone was prepared as in example 5 but startingfrom (S)-4-isopropyl-2-oxazolidinine. Following the procedure of D. A.Evans et al. (J. Am. Chem. Soc. 1990, 112, 4011), potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 7.2 mL, 3.6 mmol) wasdiluted with anhydrous THF (10 mL), and the solution was cooled underargon to −78 ° C. The oxazolidinone (1.00 g, 3.25 mmol) in THF (10 mL),also at −78° C., was cannulated into the base solution. After stirringat −78° C. for 30 min, a solution of trisyl azide (3.9 mmol, 1.21 g) inTHF (10 mL) also at −78 C., was cannulated into the reaction mixture.The mixture was then stirred until completion (TLC) and then thereaction was quenched at −78° C. with glacial AcOH (0.86 mL, 15 mmol).The reaction was warmed to room temperature and stirred overnight.Volatiles were removed under reduced pressure and the residue extractedinto EtOAc. After washing with water, drying (MgSO₄) and concentration,the residue was purified by flash chromatography on silica gel using 30%EtOAc in hexane (61% yield).

(S)-3-[(S)-2-Amino-2-(3,4-dimethoxyphenyl)-ethanoyl]-4-isopropyl-oxazolidin-2-one

Following the procedure of D. A. Evans et al. (J. Am. Chem. Soc. 1990,112, 401 1), the azido derivative from above (0.100 g, 0.28 mmol) and20% palladium hydroxide on carbon (20 mg) were suspended in MeOH (5 mL)and trifluoroacetic acid (3 equivalents, 0.86 mmol, 66 μL) was added.The mixture was hydrogenated under 1 atm of hydrogen gas for 3 h. Themixture was filtered and volatiles removed under vacuo, to give thedesired amine in quantitative yield, as a white solid.

(S)-f11-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-yl)-methanoyl]-amino}-(3,4-dimethoxyphenyl)aceticacid

The acid derivative of example 2 (0.100 g, 0.32 mmol), the aminederivative from above (1.1 equivalent, 0.114 g, 0.36 mmol) and TBTU (1.3equivalent, 0.134 g, 0.42 mmol) were dissolved in DMF (0.5 mL) andtriethylamine (4 equivalents, 180 μL, 1.29 mmol) was added. The mixturewas stirred at room temperature until reaction was complete asdetermined by HPLC analysis. 1 N NaOH (0.5 mL) was then added and thereaction mixture added to water (25 mL) with vigorous stirring. Theresulting precipitate was collected, washed with water and dried (198mg, 95% yield). This material was dissolved in THF (2.5 mL) and water(0.75 mL) was added. The solution was cooled in ice and 30% aqueoushydrogen peroxide (4 equivalents, 151 μL) was added followed by LiOHmonohydrate (2 equivalents, 0.016 g). After stirring for 4 h at 0° C.,the reaction was quenched by addition of sodium bisulfite (3equivalents) and the THF layer separated. This solution was diluted withDMSO and the product isolated by preparative HPLC (45 mg).

Example 8 (Entry 1040, Table 1)(S)2-([1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)methanoyl]amino)-3-(4-hydroxyphenyl)propionicacid

The carboxylic acid of example 2 (0.075 g, 0.24 mmol) and TBTU (1.2equiv., 0.29 mmol, 0.093 g) were dissolved in DMF (0.5 mL) and DIEA (5equiv., 1.2 mmol, 0.21 mL) was added followed by tyrosine methyl esterhydrochloride (1.2 equiv., 0.29 mmol, 0.036 g). The mixture was stirred30 min at room temperature. The reaction mixture was added drop-wise to1 N NaOH (10 mL) and the mixture stirred until complete hydrolysis ofthe methyl ester (as determined by HPLC analysis). The pH of thesolution was then adjusted to 5-6 by drop-wise addition of 1 NHCl. Thegray precipitate that formed was collected by filtration, washed withwater and dried (125 mg). The solid was further purified byreversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients togive after lyophilisation, the TFA salt of the title compound as a whiteamorphous solid (35 mg).

Example 9 (Entry 16011, Table 16)(S)-3-(4-Carboxymethoxyphenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)methanoyl]amino}propionicacid

The carboxylic acid of example 2 (0.075 g, 0.24 mmol) and TBTU (1.3equiv., 0.31 mmol, 0.100 g) were dissolved in DMSO (0.5 mL) and DIEA (5equiv., 1.2 mmol, 0.21 mL) was added followed by tyrosine benzyl esterpara-toluenesulfonate (1.3 equiv., 0.31 mmol, 0.137 g). The mixture wasstirred overnight at room temperature and then added drop-wise to asolution of AcOH (0.3 mL) in water (15 mL). The gray precipitate thatformed was collected by filtration, washed with water and dried (137mg).

A portion of the tyrosine benzyl ester derivative from above (0.030 g,0.043 mmol) was dissolved in acetone (1.5 mL) and Cs₂CO₃ (6 equiv., 0.26mmol, 0.090 g) and methylbromoacetate (2 equiv., 0.086 mmol, 0.08 mL)were added. The mixture was stirred at 50° C. for 30 min and volatilesremoved under reduced pressure. The residue was dissolved in DMSO (0.30mL) and 5 N NaOH (50 μL) and water (50 μL) were added. The mixture wasstirred at room temperature for 30 min, acidified with TFA (50 μL) anddiluted with DMSO (0.15 mL). The mixture was directly purified byreversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients togive after lyophilisation, the TFA salt of the title compound as a whiteamorphous solid (18 mg).

In a similar fashion, the tyrosine phenolic group could be alkylatedwith ethyl 4-bromopyruvate or methyl 5-bromovalerate to give inhibitorswith homologated alkylcarboxyl chains.

Example 10 (Entry 16017, Table 16)(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)methanoyl]amino}-3-[4-(1H-tetrazol-5-yl)phenyl]propionicacid

(S)-4-Cyanophenylalanine ethyl ester hydrochloride

(S)-4-Cyanophenylalanine (0.630 g, 3.31 mmol) was suspended in EtOH (25mL) and amberlyst-15 ion-exchange resin (10 g) was added. The mixturewas stirred for two days at room temperature and quenched by addition of10% aqueous NaHCO₃ (50 mL). The mixture was extracted twice with DCM (50mL) and the organic extract dried over MgSO₄. Hydrogen chloride in Et₂O(1 M, 10 mL) was added and volatiles removed under reduced pressure togive (S)-4-cyanophenylalanine ethyl ester hydrochloride as a white solid(0.800 g, 94% yield).

(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]amino}propionicacid ethyl ester

The carboxylic acid of example 2 (0.060 g, 0.20 mmol) and TBTU (1.3equiv., 0.26 mmol, 0.084 g) were dissolved in DMSO (0.6 mL) and DIEA (5equiv., 1.0 mmol, 0.18 mL) was added followed by(S)-4-cyanophenylalanine ethyl ester hydrochloride (1.3 equiv., 0.26mmol, 0.065 g). The mixture was stirred at room temperature for 1 h andquenched with water. The precipitated solid was collected by filtration,washed with water and dried. The title amide (0.081 g) was obtained as abeige solid.

(S)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5yl)methanoyl]amino}3-[4-(1H-tetrazol-5-yl)phenyl]propionicacid ethyl ester

(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid ethyl ester from above (0.260 g, 0.51 mmol) and tributyltin azide(4 equiv., 2.0 mmol, 0.650 g) were dissolved in DMSO (2 mL) and thesolution stirred at 80° C. for 48 h. The reaction was then quenched with1 N HCl (10 mL) and stirred for an additional 40 min. The aqueous phasewas decanted and the oily residue dissolved in DMSO and purified byreversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients togive after lyophilisation, the TFA salt of the title compound as a whiteamorphous solid (97 mg).

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)methanoyl]amino}-3-[4-(1H-tetrazol-5-yl)phenyl]propionicacid

The ethyl ester prepared as above (0.16 mmol) was dissolved in DMSO (1mL) and aqueous KOH was added (pH 10). After stirring for 30 min at roomtemperature, the mixture was acidified with TFA and the precipitatecollected by filtration. The product was purified by reversed-phase HPLCusing 0.1% TFA—0.1% TFA in acetonitrile gradients to give afterlyophilisation, the TFA salt of the title compound as a white amorphoussolid (15 mg).

Example 11 2,6-Dimethyl-DL-tyrosine methyl ester hydrochloride

The amino acid of example 11 was prepared in racemic form following theprocedure of Dygos et al. (Synthesis 1992, 741).Bis(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate was used ascatalyst and 1,2-bis(diphenylphosphino)ethane as ligand for thehydrogenation step. The amino acid was converted to its methyl esterhydrochloride in the usual manner (MeOH/SOCl₂). This amino acidderivative was used to prepare inhibitors in the usual manner.

Example 12 3,5-Dimethyl-DL-tyrosine methyl ester hydrochloride

This compound was prepared from 2,6-dimethyl-4-iodophenol, using theprocedure described for example 11.

Example 13 N-Boc-4-(2-Carboethoxyethenyl)-L-phenylalanine benzyl esterand N-Boc-4-(2-Carboethoxycyclopropyl)-L-phenylalanine benzyl ester

N-Boc-4-Iodo-L-phenylalanine benzyl ester

N-Boc-4-iodophenylalanine was dissolved in acetonitrile and DBU (1equivalent) was added followed by benzyl bromide (1 equivalent). Themixture was stirred for 2 h at room temperature. After removal of thesolvent under reduced pressure, the residue was dissolved in EtOAc andthe solution washed with 10% aqueous HCl and water. Drying (MgSO₄) andconcentration under reduced pressure gave a crude product that waspurified by crystallization from hexane.

N-Boc-4-Formyl-L-phenylalanine benzyl ester

The iodo derivative from above (6.16 g, 12.8 mmol) was dissolved in dryTHF (50 mL). The system was purged with carbon monoxide gas.Tetrakis(triphenylphosphine)palladium (300 mg) was added and the mixturestirred for 10 min at room temperature, and then brought to 50° C.Tributyltin hydride (4.10 g, 14 mmol) in THF (20 mL) was added drop-wiseover 2.5 h while CO gas was slowly bubbled through the solution. Aftercompletion, THF was removed under reduced pressure and the residuepurified by flash chromatography using 20% EtOAc in hexane as eluent.The title compound was obtained as a tan-colored solid (4.33 g, 88%yield).

(E)-3-[4-((S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)phenyl]-acrylicacid ethyl ester

The aldehyde from above (0.500 g, 1.3 mmol) and(carbethoxymethylene)triphenylphosphorane (0.905 g, 2.60 mmol) weresuspended in toluene (4 mL) and the mixture heated to 80° C. for 2 h.Toluene was removed under reduced pressure and the residue purified byflash chromatography on silica gel using 30-50% EtOAc in hexane aseluent. The unsaturated ester was obtained as a solid in quantitativeyield.

2-[4-((S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-phenyl]-cyclopropanecarboxylic acid ethyl ester

The ester from above (0.040 g, 0.088 mmol) was dissolved in 1:1 DCM-Et₂O(0.5 mL) and palladium acetate (10 mg) was added. The solution wascooled to −5° C. and excess diazomethane in Et₂O was added slowly. Afterstirring for 15 min, the solution was flushed with air, filtered andconcentrated in vacuo. The title compound was obtained in quantitativeyield.

Example 14 (R)-2-(4-Hydroxyphenyl)-1-methyl-ethyl-ammonium chloride

N-Boc-(O-benzyl)-L-tyrosine was reduced to the corresponding aminoalcohol, converted to the mesylate and then the ethyl sulfide, followingthe procedure of Donner (Tetrahedron Lett. 1995, 36, 1223). The ethylsulfide was reduced to a methyl group using nickel boride according toEuerby and Waigh (Synth. Commun. 1986, 16, 779). The O-benzyl protectinggroup was also cleaved in this step.

The N-Boc protecting group was removed with hydrogen chloride to givethe crude to amine hydrochloride salt that was used withoutpurification.

Example 15(S)-1-Methoxycarbonyl-2-[4-(4-methoxycarbonyl-[1,2,3]triazol-1-yl)-phenyl]-ethylammonium chloride

4-Azido-L-phenylalanine hydrochloride (0.242 g, 1 mmol) was dissolved indry DMF (1 mL) and methyl propiolate (0.420 g, 5 mmol) was added. Thesuspension was stirred 24 h at 45° C. After cooling to room temperature,the solid was filtered, washed with EtOAc and dried (175 mg). Thematerial was suspended in MeOH (15 mL) and thionyl chloride (0.5 mL) wasadded drop-wise. The mixture was refluxed for 3 h, cooled andconcentrated under reduced pressure. The residue was triturated withether to give the title compound as a white solid (175 mg, 53% yield).

Example 16 (Entry 1083, Table 1)[4-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]aminoethyl)-phenyl]-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylicacid

The carboxylic acid of example 2 was coupled to 4-azido-L-phenylalaninemethyl ester hydrochloride using the usual procedure. The resultingamide derivative (0,020 g, 0.039 mmol) was dissolved in DMF (0.3 mL) andethyl 4,4,4-trifluoro-2-butynoate (0.014 g, 0.084 mmol) was added. Themixture was stirred overnight at 60° C. The reaction mixture was thenevaporated under high vacuum and the residue dissolved in DMSO (0.3 mL).Aqueous 5 N NaOH (0.2 mL) was added and the mixture stirred at roomtemperature for 1 h. The title compound was isolated by preparative HPLCof the reaction mixture.

Example 17 (Entry 16022, Table 16)(S)-2-{[1(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-[4-(1H-tetrazol-5-ylmethoxy)-phenyl]-propionicacid

(S)-2-tert-Butoxycarbonylamino-3-(4-cyanomethoxyphenyl)-propionic acidbenzyl ester

N-Boc-L-tyrosine benzyl ester (0.371 g, 1 mmol) was dissolved in acetone(5 mL) and cesium carbonate (0.650 g, 2 mmol) was added followed bychloroacetonitrile (0.150 g, 2 mmol). The mixture was then reflux for 2h. The reaction was cooled to room temperature and insoluble saltsremoved by filtration using acetone for washings. Volatiles were removedunder reduced pressure and the residue dissolved in DCM. The solutionwas washed with brine, dried (MgSO₄) and concentrated to give thedesired product as an oil (450 mg).

Coupling with Carboxylic Acid of Example 2

The above ester was stirred for 1 h in 4 N HCl-dioxane. Volatiles wereremoved under reduced pressure and the residue triturated with Et₂O togive the amine hydrochloride salt as a tan-colored solid (350 mg).

The hydrochloride salt (0.080 g, 0.26 mmol) was added to a mixture ofthe carboxylic acid of example 2 (0.060 g, 0.2 mmol), TBTU (0.080 g,0.26 mmol) and DIPEA (150 μL) in DMSO (0.9 mL). The mixture was stirredfor 1 h at room temperature and then poured into water. The precipitatedmaterial was collected by filtration, washed with water and dried. Itwas purified by flash chromatography on silica gel using EtOAc aseluent, to give the desired amide derivative (50 mg).

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-[4-(1H-tetrazol-5-ylmethoxy)-phenyl]-propionicacid

The cyano derivative from above (0.040 g, 0.066 mmol) and tributyltinazide (300 mg) were dissolved in DMSO (0.5 mL) and the mixture stirredat 80° C. for 24 h. Aqueous 6 N HCl (1 mL) was added and the mixturestirred for 1 h at room temperature. The mixture was basified to pH 10with 5 N NaOH, and after stirring for 30 min, the solution was acidifiedwith TFA and the precipitated material collected by filtration. Thetitle compound was isolated by preparative HPLC (6.6 mg).

Example 18 4-Aminophenylalanine derivatives

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-(4-nitrophenyl)-propionicacid methyl ester

The carboxylic acid of example 2 (0.500 g, 1.61 mmol), TBTU (0.621 g,1.94 mmol) and 4-nitro-L-phenylalanine methyl ester hydrochloride (0.461g, 1.77 mmol) were dissolved in DMSO (2.0 mL) and DIEA (6.44 mmol, 1.12mL) was added. The mixture was stirred for 2 h at room temperature(HPLC: complete). The reaction mixture was added drop-wise with stirringto a mixture of water (45 mL) and AcOH (0.8 mL). The precipitate thatformed was collected by filtration, washed with water and dried (0.768g, 92% yield).

(S)-3-(4-Aminophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid methyl ester

The nitro derivative from above (0.765 g, 1.48 mmol) was hydrogenated inMeOH (25 mL) over 10% palladium on carbon (150 mg) under 1 atm H₂ for 6h (HPLC: complete). The catalyst was removed by filtration and volatilesremoved under vacuum to give the desired aniline in quantitative yieldas a greenish-brown solid.

(Entry 16032, Table 16):(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-(4-methanesulfonylaminophenyl)-propionicacid (W=SO₂CH₃)

The aniline derivative from above (0.050 g, 0.10 mmol) was dissolved inDCM (5 mL). DIEA (1.1 equivalent, 0.11 mmol, μL) was added and thesolution cooled in ice. Methanesulfonyl chloride (1.1 equivalent, 0.11mmol, 9 μL) was added. Stir 1 h at 0° C. Add DIEA (20 μL) andmethanesulfonyl chloride (4 μL) and stir an additional h at roomtemperature. Evaporate DCM under reduced pressure and dissolved residuein DMSO (1.4 mL). 2.5 N Aqueous NaOH (200 μL) was added and the mixturestirred 1 h at room temperature (hydrolysis of methyl ester complete byHPLC). TFA (100 μL) was added, the solution was filtered and the productisolated by prep HPLC (17 mg).

(Entry 16031, Table 16):(S)-3-(4-Acetylaminophenyl)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (W=COCH₃)

The procedure described above was followed, using acetyl chloride asacylating agent.

(Entry 1080, Table 1):(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]amino}-3-{4-[(1-phenylmethanoyl)-amino}-phenyl]-propionicacid (W=COPh)

The procedure described above was followed, using benzoyl chloride asacylating agent.

(Entry 16030, Table 16):(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]amino}-3-(4-trifluoromethanesulfonylaminophenyl)-propionicacid (W=SO₂CF₃)

The procedure described above was followed, usingtrifluoromethanesulfonic anhydride as acylating agent.

(Entry 16009, Table 16):(S)-3{4-[(1-Carboxymethanoyl)amino]phenyl}-2--{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (W=COCO₂H)

The procedure described above was followed, using methyloxalyl chlorideas acylating agent.

(Entry 16028, Table 16):(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-(4-formylaminophenyl)-propionicacid (W=CHO)

The aniline derivative described at the start of example 18 (0.050 g,0.103 mmol) was dissolved in MeOH (1 mL) and methyl formate (300 μL) wasadded. The mixture was stirred for 48 h at 50° C. (HPLC indicates 75%conversion). Volatiles were removed under reduced pressure and theresidue was dissolved in a mixture of DMSO (1 mL) and 2.5 N NaOH (200μL). After stirring for 1 h at room temperature, TFA (100 μL) was addedand the product isolated by prep HPLC (16 mg).

(Entry 16026, Table 16):(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-(4-ureidophenyl)-propionicacid (W=CONH₂)

The aniline derivative described at the start of example 18 (0.050 g,0.103 mmol) was dissolved in AcOH (0.5 mL) and KOCN (3 equivalent, 0.309mmol, 0.024 g) was added. The mixture was stirred for 2 h at roomtemperature (HPLC: complete). Volatiles were removed under vacuo and theresidue was dissolved in a mixture of DMSO (0.5 mL) and 2.5 N NaOH (200μL). The mixture was stirred for 1 h at room temperature and TFA (100μL) was added. The product was isolated by Prep HPLC (22 mg).

(Entry 16010, Table 16):(S)-3-[4-(Carboxymethylamino)phenyl]-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (W=CH₂CO₂H)

The aniline derivative described at the start of example 18 (0.040 g,0.082 mmol) was dissolved in a mixture of DCM (2 mL) and DMSO (0.5 mL).DIEA (2 equivalent, 0.16 mmol, 29 μL) and methyl bromoacetate (1.1equivalent, 0.09 mmol, 9 μL) were then added and the mixture stirred 48h at room temperature. DCM was removed under reduced pressure and 5 NNaOH (50 μL) was added. After stirring for 0.5 h at room temperature,the reaction mixture was acidified with TFA (50 μL) and the product wasisolated by prep HPLC (7 mg).

Example 19 (Entry 16029, Table 16)(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]amino}-3-[4-(2-hydroxy-3,4-dioxocyclobut-1-enylamino)-phenyl]-propionicacid

The aniline of example 17 (0.050 g, 0.103 mmol) was dissolved in MeOH (2mL) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (3 equivalents, 0.31 mmol,0.044 g) was added. The mixture was refluxed for 2 h (HPLC: complete).MeOH was removed under reduced pressure and the residue purified by prepHPLC. The most polar component was isolated (corresponds to the methylester on the amino acid carboxyl group) and stirred with DMSO (0.5 mL)and 2.5 N NaOH (200 μL) for 0.5 h. TFA 100 μL) was added and the desiredcompound of example 19 was isolated by prep HPLC.

Example 20 (Entry 11021, Table 11)(S)-2-(5-Hydroxy-1-methyl-1H-indol-3-yl)-1-methoxycarbonyl-ethyl-ammoniumchloride and(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino]-3(5-hydroxy-1-methyl-1H-indol-3-yl)-propionicacid)

5-Benzyloxy-1-methylindole

5-benzyloxyindole (2.00 g, 8.96 mmol) was dissolved in DMF (20 mL) andthe solution cooled in ice. Sodium hydride (60% oil dispersion, 1.2equivalent, 10.7 mmol, 0.43 g) was added and the mixture stirred for 30min. Iodomethane (1.2 equivalent, 10.7 mmol, 0.67 mL) was added and thereaction stirred at room temperature overnight. The reaction was thenpoured into water (150 mL) and the precipitated solid collected byfiltration. After washing with water and drying,5-benzyloxy-1-methylindole (1.913 g, 90% yield) was obtained as a whitesolid.

(S)-2-(5-Hydroxy-1-methyl-1H-indol-3-yl)-1-methoxycarbonyl-ethyl-ammoniumchloride

Following the procedure of Bennani et al. (Synlett 1998, 754),5-benzyloxy-1-methylindole was converted to the N-Cbz protectedtryptophan benzyl ester derivative in 20% yield: MS (ES⁺) m/z 549 (MH⁺).Protecting groups were removed by hydrogenolysis in MeOH over 10%palladium under 1 atm H₂ and the free amino acid converted to thecorresponding methyl ester hydrochloride in the usual manner usingMeOH/thionyl chloride.

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino]-3(5-hydroxy-1-methyl-1H-indol-3-yl)-propionicacid

The above tryptophan derivative was coupled in the usual manner to thecarboxylic acid of example 2 to give the title compound after hydrolysisof the methyl ester.

Example 21 (Entry 11020, Table 11)(S)-2-(5-Hydroxy-2-methyl-1H-indol-3-yl)-1-methoxycarbonyl-ethyl-ammoniumchloride and(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino]-3-(5-hydroxy-2-methyl-1H-indol-3-yl)-propionicacid

(S)-2-(5-Hydroxy-1-methyl-1H-indol-3-yl)-1-methoxycarbonyl-ethyl-ammoniumchloride

Ethyl 5-hydroxy-2-methyl-3-carboxylate was converted to the 5-benzyloxyderivative (benzyl chloride/K₂CO₃/acetonitrile) and decarboxylated togive 5-benzyloxy-2-methylindole (R. V. Heinzelman et al., J. Org. Chem.1960, 25, 1548) which was then was converted to the correspondingtryptophan derivative as described for example 20.

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino]-3-(5-hydroxy-2-methyl-1H-indol-3-yl)-propionicacid

The above tryptophan derivative was coupled in the usual manner to thecarboxylic acid of example 2 to give the title compound after hydrolysisof the methyl ester.

Example 22 (Entry 11022, Table 11)(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-[5-(1H-tetrazol-5-yl)-1H-indol-3-yl]-propionicacid

(S)-5-Cyanotryptophan methyl ester hydrochloride was prepared accordingto the procedure of Dua and Phillips (Tetrahedron Lett. 1992, 33, 29),and coupled to the carboxylic acid of example 2 in the usual manner. Thecyano group was then converted into the corresponding tetrazole asdescribed in example 10 and the title compound was isolated in the usualmanner.

Example 233-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indole-5-carboxylicacid (Entry 24, Table 1) and(S)-3-(5-carbamoyl-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 11019, Table 11)

(S)-3-(1-Acetyl-5-cyano-1H-indol-3-yl)-2-methoxycarbonylamino-propionicacid methyl ester was prepared following the procedure of Dua andPhillips (Tetrahedron Lett. 1992, 33, 29). The cyano derivative wasstirred at 80° C. for 18 h with concentrated HCl. Removal of thevolatiles under reduced pressure gave a 2:1 mixture of5-carboxytryptophan and 5-tryptophan carboxamide. The mixture wasconverted to the methyl ester (MeOH/SOCl₂) and these were coupled to thecarboxylic acid of example 2 in the usual manner. After hydrolysis ofthe methyl esters, the title compounds were separated by prep HPLC.

3-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indole-5-carboxylicacid (Entry 11018, Table 11)(S)-3-(5-carbamoyl-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 11019, Table 11) Example 24 (Entry 2062, Table 2)1-Cyclohexyl-2-{4-[(3-dimethylamino-propylcarbamoyl)-methoxy]-phenyl}-1H-benzoimidazole-5-carboxylicacid 3,4-dimethoxybenzyl amide

2-(4-Carboxymethoxy-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylicacid ethyl ester (Entry 11007, Table 11)

Following the procedure of example 1, ethyl3-amino-4-(aminocyclohexyl)benzoate (1.077 g, 4.1 mmol) and4-formylphenoxyacetic acid (0.748 g, 4.15 mmol) were dissolved in amixture of DMF (8 mL) and water (0.5 mL). Oxone® (0.7 equivalent, 2.87mmol, 1.764 g) was added and the mixture stirred for 30 min at roomtemperature (HPLC: complete). Water was added to precipitate theproduct, which was collected by filtration, washed with water and dried(1.130 g, 65% yield, brown solid).

1-Cyclohexyl-2-{4-[(3-dimethylamino-propylcarbamoyl)-methoxy]-phenyl}-1H-benzoimidazole-5-carboxylicacid ethyl ester

The acid from above (0.975 g, 2.31 mmol), TBTU (0.963 g, 3.0 mmol) andtriethylamine (0.98 mL, 7.0 mmol) were dissolved in DMF (4 mL) and3-dimethylaminepropylamine (0.32 mL, 2.5 mmol) was added. The mixturewas stirred for 6 h at room temperature and quenched with 1 N NaOH (1mL). Water was added and the product extracted with EtOAc. The extractwas washed with water, dried (MgSO₄) and concentrated to a dark purpleoil.

1-Cyclohexyl-2-{4-[(3-dimethylamino-propylcarbamoyl)-methoxy]-phenyl}-1H-benzoimidazole-5-carboxylicacid 3,4-dimethoxybenzyl amide (Entry 2062, Table 2)

The above ethyl ester (0.598 g, 1.18 mmol) was dissolved in MeOH and 1 NLiOH (2 equivalent, 2.36 mmol, 2.36 mL) was added. The mixture wasstirred overnight at room temperature, volatiles removed under reducedpressure and the residue dried in vacuo at 45° C.

The lithium salt from above (0.098 mmol) in DMSO (0.29 molar) wastreated with TBTU (0.148 mmol, 0.047 g), triethylamine (0.197 mmol,0.027 mL) and veratrylamine (0.108 mmol, 16 μL). The mixture was stirredovernight at room temperature, poured into 0.5 N NaOH (10 mL) andextracted into EtOAc. The extract was washed with water, dried (MgSO₄)and concentrated. The residue was purified by prep HPLC (29 mg).

Example 25 (Entry 16035, Table 16)(S)-3-(4-Carbamoyl-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid

(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid ethyl ester from example 10 (0.120 g, 0.235 mmol) was dissolved ina mixture of acetone (5 mL) and water (3 mL). Urea-hydrogen peroxidecomplex (1.0 mmol, 0.094 g) and potassium carbonate (10 mg) were addedand the mixture stirred until completion (HPLC). The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inDMSO (1.5 mL) and 5 N NaOH (0.2 mL) was added. After stirring for 30 minat room temperature, TFA (0.5 mL) was added and the product isolated byprep HPLC (18 mg).

Example 26(E)-3-[5-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-hydroxyphenyl]-acrylicacid 26 (Entry 16064, Table 16) and(S)-3-[-3-(2-caboxyethyl)-4-hydroxy-phenyl]-2-{[-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 16065, Table 16)

(S)-3-(4-Acetoxy-3-iodo-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester

3-Iodo-L-tyrosine was converted to the methyl ester and protected onnitrogen with a Boc group following standard procedures. The hydroxylgroup was then acetylated with acetic anhydride in DMF, in the presenceof DIEA.

(E)-3-[2-Acetoxy-5-((S)-2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl]-acrylicacid methyl ester

The iodo derivative from above (0.150 g, 0.32 mmol) was dissolved inMeCN (3 mL) and argon was bubbled through the solution for 15 min.Methyl acrylate (5 equivalent, 1.62 mmol, 146 μL), tri-o-tolylphosphine(50 mg), racemic BINAP (50 mg), DIEA (2.6 equivalent, 0.84 mmol, 146 μL)and palladium acetate (50 mg) were added and the mixture refluxed for 5h. The reaction was cooled to room temperature and argon was bubbledagain through the solution for 5 min. Fresh portions of methyl acrylate(146 μL), DIEA (146 μL), tri-o-tolylphosphine (50 mg), racemic BINAP (50mg) and palladium acetate (50 mg) were added and refluxing resumed foranother 16 h. Volatiles were then removed under reduced pressure and theresidue dissolved in EtOAc. The solution was washed with 1 M KHSO₄, 5%NaHCO₃ and brine, dried (MgSO₄) and concentrated. The product waspurified by flash chromatography using 10-25% EtOAc in hexane (122 mg,90% yield).

(S)-3-[4-Acetoxy-3-(2-methoxycarbonyl-ethyl)-phenyl]-2-tert-butoxycarbonylamino-propionicacid methyl ester

The acrylate from above (0.060 g, 0.14 mmol) was hydrogenated in iPrOH(3 mL) under 1 atm H₂ over 10% palladium on carbon (50 mg). After 16 h,the solution was filtered and volatiles removed under reduced pressureto give the saturated analogue (56 mg).

(E)-3-[5-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-hydroxyphenyl]-acrylicacid

The acrylate derivative from above (0.060 g, 0.14 mmol) was stirred for1 h in 4N HCl in dioxane (2 mL). Volatiles were then removed in vacuoand the residue dissolved in DMSO (1 mL). TBTU (1.5 equivalent, 0.067mg, 0.21 mmol), DIEA (4 equivalent, 0.56 mmol, 97 μL) and the carboxylicacid of example 2 (1.2 equivalent, 0.17 mmol, 0.052 g) were added andthe mixture stirred for 1.5 h at room temperature. 2 N NaOH (200 μL) andMeOH (400 μL) were added and the mixture stirred overnight at roomtemperature. The title compound was isolated by prep HPLC (27 mg).

(S)-3-[-3-(2-caboxyethyl)-4-hydroxy-phenyl]-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid

The propanoate derivative from above (0.056 g, 0.13 mmol) was stirredfor 1 h in 4N HCl in dioxane (2 mL). Volatiles were then removed invacuo and the residue dissolved in DMSO (1 mL). TBTU (1.5 equivalent,0.064 mg, 0.20 mmol), DIEA (4 equivalent, 0.53 mmol, 92 μL) and thecarboxylic acid of example 2 (1.2 equivalent, 0.16 mmol, 0.049 g) wereadded and the mixture stirred for 1.5 h at room temperature. 2 N NaOH(200 μL) and MeOH (400 μL) were added and the mixture stirred overnightat room temperature. The title compound was isolated by prep HPLC (34mg).

Example 27 (Entry 16024, Table 16)(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-3-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]propionicacid

The acid of example 2 and 4-formyl-L-phenylalanine benzyl esterhydrochloride (example 13) were coupled with TBTU in the usual manner.The aldehyde derivative thus obtained (0.050 g, 0.087 mmol) andrhodamine (1.1 equivalent, 0.013 g, 0.095 mmol) were suspended in EtOH(0.5 mL) and piperidine (10 μL) was added. The mixture was refluxed for3 h. DMSO (1 mL) and 2 N NaOH (0.3 mL) were added and the mixturestirred overnight at room temperature. The reaction mixture wasneutralized with TFA and the product isolated by prep HPLC (6 mg).

Example 283-Cyclohexyl-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

Ethyl 5-amino-6-cyclohexylaminonicotinate

Ethyl 6-chloro-5-nitronicotinate (1.00 g, 4.33 mmol) prepared accordingto A. H. Berrie et al. (J. Chem. Soc. 1951, 2590) was dissolved in DMSO(2 mL) and cyclohexylamine (0.54 g, 5.4 mmol) was added. The mixture wasstirred for 1 h at room temperature, diluted with water and the yellowprecipitated collected by filtration. The product was washed with waterand dried (0.95 g, 74% yield).

The nitro derivative from above (0.68 g, 2.32 mmol) was hydrogenated (1atm H₂) in EtOAc (30 mL) over 5% palladium on charcoal (100 mg). After 2h, the reaction (complete by HPLC) was filtered and concentrated underreduced pressure to give the title diamine (0.58 g, 94% yield.

3-Cyclohexyl-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

The diamine from above (0.58 g, 2.2 mmol) and 2-pyridine carboxaldehyde(0.252 g, 2.4 mmol) were dissolved in a mixture of DMF (2 mL) and water(0.1 mL). Oxone® (1.24 g, 2 mmol) was added and the mixture stirred for2 h at room temperature. The reaction was diluted with 5% aqueous NaHCO₃and extracted with DCM. The extract was washed with water and brine,dried (MgSO₄) and concentrated to a brown oil.

The crude ester was dissolved in MeOH (30 mL) and KOH (300 mg) wasadded. The mixture was refluxed for 2 h, cooled and concentrated underreduced pressure. The residue was dissolved in water (20 mL) and thesolution acidified with 4 N HCl until complete precipitation of theproduct as a purple solid. The crude product was collected, washed withwater an dried. It was further purified by prep HPLC.

Example 29 (Entry 16002, Table 16)(S)-3-(4-Carboxymethyl-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}propionicacid

The protected 4-carboxymethyl-L-phenylalanine derivative was prepared byadaptation of the procedure of J. W. Tilley et al. (J. Org. Chem. 1990,55, 906). Following deprotection on the carbamate function with HCl, theamine hydrochloride was coupled in the usual manner to the acid ofexample 2. Deprotection of all ester functions with NaOH andpurification by prep HPLC gave the title compound:

Example 30 Racemic1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylicacid[2,2,2-trifluoro-1-(4-hydroxy-benzyl)-ethyl]-amide and[4-(2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3,3,3-trifluoro-propyl)-phenoxy]-aceticacid (Entries 1122 and 1123, Table 1)

Racemic 1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylicacid[2,2,2-trifluoro-1-(4-hydroxy-benzyl)-ethyl]-amide (Entry 1122,Table 1)

The racemic O-methyl trifluoromethyl amine derivative, prepared by theprocedure of R. M. Pinder et al. (J. Med. Chem. 1969, 12, 322), wasdeprotected by stirring with 48% aqueous HBr at 100° C. for two hours.The resulting hydrobromide salt was coupled in the usual manner to theacid of example 2 to give after preparative C18 reversed-phase HPLCpurification the title phenolic compound.

Racemic[4-(2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3,3,3-trifluoro-propyl)-phenoxy]-aceticacid: (Entry 1123, Table 1)

The racemic trifluoromethyl amine hydrobromide salt from above (0.64 g,2.23 mmol) was dissolved in 80% aqueous MeCN and the solution cooled inice. Sodium bicarbonate (0.50 g, 6 mmol) was added followed bydi-tert-butyldicarbonate (0.48 g, 2.23 mmol), and the mixture wasstirred for 15 min at 0° C. and 4 h at room temperature. The reactionmixture was then poured into water (60 mL) and extracted with EtOAc(3×). The extract was washed with water, dried (MgSO4) and concentratedto an oily residue that was purified by flash chromatography using 3:7EtOAc/hexane as eluent (tan-colored solid, 270 mg).

The carbamate from above (0.260 g, 0.85 mmol) was dissolved in acetone(5 mL). Anhydrous potassium carbonate (0.280 g, 2.0 mmol) and methylbromoacetate (0.150 g, 1 mmol) were added and the mixture was refluxedfor 1.5 h. The reaction mixture was then diluted with acetone andfiltered. Concentration of the filtrate gave the desired aryloxyacetatederivative as a white solid (0.31 g).

The carbamate from above (0.310 g, 0.82 mmol) was deprotected bystirring in 4N HCl-dioxane (10 mL) for 1 h at room temperature. Removalof volatiles under reduced pressure gave the amine hydrochloride salt asa yellow solid (0.250 g).

The amine salt from above was coupled in the usual manner to the acid ofexample 2. Deprotection of the ester function with NaOH and purificationby preparative C18 reversed-phase HPLC gave the title compound.

Example 312-[2-(4-{1-Cyclohexyl-5-[(S)-1-methoxycarbonyl-2-(5-methoxycarbonylmethoxy-1H-indol-3-yl)-ethylcarbamoyl]-1H-benzimidazol-2-yl}-phenoxy)-ethanoylamino]-ethyl-ammoniumchloride

4-Chloro-3-nitrobenzoyl chloride

4-Chloro-3-nitrobenzoic acid (40.40 g, 0.20 mole) was suspended in DCM(100 mL) containing 3 drops of DMF. Oxalyl chloride (1.5 equivalents,0.3 mole, 27 mL) was added in small portions and the mixture stirredovernight at room temperature. After refluxing for an additional hour tocomplete the reaction, volatiles were removed under reduced pressure andthe residue was coevaporated twice with hexane to give the titlecompound as a light yellow solid.

(S)-1-Methoxycarbonyl-2-(5-methoxycarbonylmethoxy-1H-indol-3-yl)-ethyl-ammoniumchloride

(S)-5-Hydroxytryptophan methyl ester hydrochloride (1.55 g, 5 mmol) wasdissolved in 80% aqueous MeCN (25 mL) and the solution cooled in ice.Sodium bicarbonate (0.850 g, 10 mmol) was added followed bydi-tert-butyldicarbonate (1.10 g, 5.1 mmol). The mixture was stirred for2 h at room temperature, poured into water (200 mL) and extracted withEtOAc (3×). The combined extracts were washed with water and brine,dried (MgSO₄) and concentrated to give a beige solid (1.65 g).

The crude product from above (1.50 g, 4.83 mmol) was dissolved inacetone (20 mL) and anhydrous potassium carbonate (1.5 g, 11 mmol) andmethyl bromoacetate (0.76 g, 5 mmol) were added. The mixture was refluxfor 4 h after which point additional methyl bromoacetate was added tocomplete the reaction (15 mg portions until complete by HPLC). Thereaction mixture was then cooled and filtered to remove solid.Evaporation of the filtrate gave the desired carbamate as an oil (2.0g).

The crude carbamate from above (2.0 g) was deprotected by stirring with4N HCl-dioxane for 1 h at room temperature. Removal of volatiles invacuo gave the desired tryptophan ester derivative as a tan-coloredsolid (1.51 g).

(S)-2-{[1-(4-Chloro-3-nitro-phenyl)-methanoyl]-amino}-3-(5-methoxycarbonylmethoxy-1H-indol-3-yl)-propionicacid methyl ester

The tryptophan derivative from above (0.343 g, 1 mmol) was dissolved in80% aqueous MeCN (10 mL) and sodium bicarbonate (3 equivalents, 0.260 g)was added. The solution was cooled in ice and 4-chloro-3-nitrobenzoylchloride (0.220 g, 1 mmol) was added. The mixture was stirred for onehour at room temperature, concentrated under reduced pressure and theresidue purified by flash chromatography (1:2 hexane/EtOAc as eluent) togive the title compound as a yellow foam (0.391 g).

(S)-2-{[1-(3-Amino-4-cyclohexylamino-phenyl)-methanoyl]-amino}-3-(5-methoxycarbonylmethoxy-1H-indol-3-yl)-propionicacid methyl ester

The 4-chlorobenzamide derivative from above (0.214 g, 0.45 mmol) wasdissolved in DMSO (1 mL) and DIEA (0.2 mL) was added followed bycyclohexylamine (3 equivalents, 0.16 mL). The mixture was stirred at60-65° C. for 4 h and subsequently diluted with water. The orangeprecipitate that formed was collected, washed with water and dried(0.200 g).

The crude material (0.200 g, 0.36 mmol) was hydrogenated (1 atm H₂) over20% Pd(OH)₂ on charcoal (60 mg) in MeOH (15 mL). After 2 h, thesuspension was filtered to remove the catalyst and concentrated undervacuo to give the title compound as a foam (0.16 g).

{2-[2-(4-Formyl-phenoxy)-ethanoylamino]-ethyl}-carbamic acid tert-butylester

4-Formylphenoxyacetic acid (0.306 g, 1.70 mmol) was dissolved in DCM (5mL). DIEA (0.524 g, 4 mmol) and TBTU (0.550 g, 1.70 mmol) were addedfollowed by tert-butyl N-(2-aminoethyl)carbamate (0.250 g, 1.56 mmol).The mixture was stirred 2 h at room temperature, dissolved in EtOAc andwashed sequentially with 5% aqueous K₂CO₃, KHSO₄, water and brine. Theextract was dried (MgSO₄) and concentrated under reduced pressure togive a yellow solid (0.350 9).

2-[2-(4-{1-Cyclohexyl-5-[(S)-1-methoxycarbonyl-2-(5-methoxycarbonylmethoxy-1H-indol-3-yl)-ethylcarbamoyl]-1H-benzimidazol-2-yl}-phenoxy)-ethanoylamino]-ethyl-ammoniumchloride

The diamine derivative (0.026 g, 0.05 mmol) and aldehyde (0.020 g, 0.06mmol) were dissolved in DMF (0.3 mL) and water (0.03 mL) was addedfollowed by oxone® (0.024 g, 0.04 mmol). The mixture was stirred 1 h atroom temperature and then diluted with water. The resulting precipitatewas collected by filtration, washed with water and dried to give a beigesolid (0.020 g).

The crude carbamate from above was stirred with TFA for 30 min at roomtemperature. Volatiles were removed under reduced pressure and theresidue was purified by preparative C18 reversed-phase HPLC to give thetitle compound of example 31 as the bis TFA salt.

Example 32(S)-3-(5-Carboxymethoxy-1H-indol-3-yl)-2-({1-[1-cyclohexyl-2-(4-{[2-(5-dimethylamino-naphthalene-1-sulfonylamino)-ethylcarbamoyl]-methoxy}-phenyl)-1H-benzimidazol-5-yl]-methanoyl}-amino)-propionicacid (Entry 2129, Table 2,)

The amine salt of example 31 (0.019 g, 0.02 mmol) was dissolved in DMSO(0.3 mL) and OIEA (0.06 mL) was added followed by dansyl chloride (0.065g, 0.02 mmol). The mixture was stirred for 1 h at room temperature. 5NNaOH (0.12 mL) and water (0.05 mL) were added and the saponification wasallowed to proceed for 1 h at room temperature. Following acidificationwith TFA, the product was directly isolated from the reaction mixture bypreparative C18 reversed-phase HPLC.

Example 335-(3-{2-[2-(4-{5-[(S)-1-Carboxy-2-(5carboxymethoxy-1H-indol-3-yl)-ethylcarbamoyl]-1-cyclohexyl-1H-benzimidazol-2-yl}-phenoxy)-ethanoylamino]-ethyl}-thioureido)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoicacid (Entry 12022, Table 12)

The amine salt of example 31 (0.06 mmol) was dissolved in DMSO (0.6 mL)and DIEA (0.3 mL) was added followed by fluorescein isothiocyanateisomer 1 (0.026 g, 0.066 mmol). The mixture was stirred for 1 h at roomtemperature. 5N NaOH (0.3 mL) and water (0.15 mL) were added andstirring resumed for an additional 30 min. Following acidification withTFA, the title compound was isolated directly by preparative C18reversed-phase HPLC.

Example 34(S)-2-{[1-(2-{4-[(2-{[1-(4-Azido-phenyl)-methanoyl]-amino}-ethylcarbamoyl)-methoxy]-phenyl}-1-cyclohexyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-carboxymethoxy-1H-indol-3-yl)-propionicacid (Entry 12025, Table 12)

4-Azido-N-{2-[2-(4-formyl-phenoxy)-ethanoylamino}-ethyl}-benzamide

4-Azidobenzoic acid (0.160 g, 1 mmol) was dissolved in DCM (3 mL). DIEA(0.5 mL, 2.5 mmol) and TBTU (0.337 g, 1.05 mmol) were added followed bytert-butyl N-(2-aminoethyl)carbamate (0.165 g, 1.03 mmol). The mixturewas stirred 2.5 h at room temperature, dissolved in EtOAc and washedsequentially with 5% aqueous K₂CO₃, KHSO₄, water and brine. The extractwas dried (MgSO₄) and concentrated under reduced pressure to give ayellow solid (0.257 g).

The crude carbamate (0.257 g, 0.84 mmol) was deprotected by stirring in4N HCl-dioxane (15 mL) for 2 h at room temperature. Volatiles wereremoved under reduced pressure to give a pinkish solid.4-Formylphenoxyacetic acid (0.200 g, 1.1 mmol) was dissolved in DCM (3mL) and DIEA (0.5 mL) was added followed by TBTU (0.350 g, 1,1 mmol) andthe amine salt from above (0.240 g, 1 mmol). The mixture was stirred 4 hat room temperature, dissolved in EtOAc and washed sequentially with 5%aqueous K₂CO₃, KHSO₄, water and brine. The extract was dried (MgSO₄) andconcentrated under reduced pressure to give an off-white solid (0.162g).

(S)-2-{[1-(2-{(4-[(2-{[1-(4-Azido-phenyl)-methanoyl]-amino}-ethylcarbamoyl)-methoxy]-phenyl}-1-cyclohexyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-carboxymethoxy-1H-indol-3-yl)-propionicacid

The benzaldehyde derivative from above (0.044 g, 0.12 mmol) and thediamine derivative of example 31 (0.052 g, 0.1 mmol) were dissolved inDMF (0.6 mL) and water (0.1 mL). Oxone® (0.050 g, 0.8 mmol) was addedand the mixture stirred for 1 h at room temperature. 5N NaOH (0.2 mL)and water (0.1 mL) were added and saponification allowed to proceed for1 h. The title compound of example 34 was isolated directly bypreparative C18 reversed-phase HPLC (12.5 mg).

Example 35(S)-3-(5-Carboxymethoxy-1H-indol-3-yl)-2-({1-[1-cyclohexyl-2-(4-{[2-({1-[4-(1-phenyl-methanoyl)-phenyl]-methanoyl}-amino)-ethylcarbamoyl]-methoxy}-phenyl)-1H-benzimidazol-5-yl]-methanoyl}-amino)-propionicacid (Entry 12026, Table 12)

The title compounds was prepared following the procedures described forexample 34 except that 4-benzoylbenzoic acid was used instead of4-azidobenzoic acid.

Example 36(S)-3-(5-Carboxymethoxy-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-{4-[2-(5-dimethylamino-naphthalene-1-sulfonylamino)-ethylcarbamoyl]-phenyl}-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 2130, Table 2)

Following the procedures described for example 34, 4-carboxybenzaldehydewas coupled to tert-butyl N-(2-aminoethyl)carbamate. Followingbenzimidazole ring formation with the diamine derivative of example 34using oxone®, the Boc protecting group was removed and the resultingamine condensed with dansyl chloride as described in example 32. Thetitle compound was obtained following saponification of the ester groupunder the usual conditions and isolation by preparative C18reversed-phase HPLC.

Example 375-[3-(2-{[1-(4-{5-[(S)-1-Carboxy-2-(5-carboxymethoxy-1H-indol-3-yl)-ethylcarbamoyl]-1-cyclohexyl-1H-benzimidazol-2-yl}-phenyl)-methanoyl]-amino}-ethyl)-thioureido]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoicacid (Entry 12021, Table 12)

The procedure described for example 36 was used except that fluoresceinisothiocyanate isomer 1 was used instead of dansyl chloride. The titlecompound of example 37 was obtained after purification by preparativeC18 reversed-phase HPLC.

Example 38 Racemic1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[2-(4-hydroxy-phenyl)-1-pyridin-2-yl-ethyl]-amide (Entry 1231, Table 1)

Triphosgene (5.45 g, 18.4 mmol) was added in small portions to anice-cold solution of triphenylphosphine (12.60 g, 48 mmol) in DCM (180mL). After stirring for 15 min, the solvent was removed under reducedpressure. A solution of 4-tert-butoxycarbonyloxy-benzyl alcohol (I.Cabrera et al., U.S. Pat. No. 5,356,752, 1994) (9.89 g, 44 mmol) in DCM(75 mL) was then added to the above residue over a 15 min period and themixture stirred for 20 min at room temperature. The solvent was thenremoved in vacuo and the residue triturated with pentane (200 mL). Thesolid was removed by filtration and washed with pentane. The combinedextracts were concentrated to 50 mL and passed through a pad of silicagel using 1:2 EtOAc-20 hexane as eluent. 4-tert-Butoxycarbonyloxy-benzylchloride was obtained as a clear yellow liquid (8.82 g).

2-(Aminomethyl)pyridine was converted to its benzaldehyde imine(benzaldehyde in DCM with 4A molecular sieves) and alkylated with4-tert-butoxycarbonyloxy-benzyl chloride following an adaptation of theprocedure described by Y. Wang et al. (Synth. Commun. 1992, 22, 265).The resulting racemic amine was coupled to the carboxylic acid ofexample 2 under the usual conditions, and deprotected with TFA to givethe title compound of example 38 after purification by preparative C18reversed-phase HPLC.

Example 39 Racemic1-cyclohexyl-2furan-3-yl-1H-benzimidazole-5-carboxylic acid[2-(4-hydroxy-phenyl)-1-phenyl-ethyl]-amide (Entry 1259, Table 1)

Following the general method of example 37, the benzaldehyde imine ofbenzylamine was alkylated with tert-butoxycarbonyloxy-benzyl chlorideusing lithium hexamethyldisilizane as a base at low temperature (−78°C.) in THF as solvent. Following the usual work up, the racemic aminewas coupled to the carboxylic acid of example 2, to give after removalof the Boc group and purification by preparative C18 reversed-phaseHPLC, the title compound of example 39.

Example 40 Racemic1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[2-(4-hydroxy-phenyl)-1-pyridin-3-yl-ethyl]-amide (Entry 1260, Table 1)

Following the procedure of example 39, but starting with3-(aminomethyl)pyridine, the title compound of example 40 was obtained.

Example 41 3-Bromomethyl-5-tert-butoxycarbonyloxy-indole-1-carboxylicacid tert-butyl ester

N-Boc-5-benzyloxy-3-methylindole was prepared according to the method ofJ. P. Marino et al. (J. Am. Chem. Soc. 1992, 114, 5566). This indole(4.00 g, 11.9 mmol) was dissolved in THF (60 mL) containingdi-tert-butyldicarbonate (2.60 g, 11.9 mmol), anhydrous K₂CO₃ (3.20 g,23 mmol), 18-crown-6 (10 mg) and 20% Pd(OH)₂ on charcoal (0.4 9). Thesuspension was stirred under a hydrogen atmosphere (1 atm) for 18 h atroom temperature. The mixture was then filtered and the cake washed withTHF. Removal of volatiles from the filtrate and purification by flashchromatography gave the Bis-Boc-protected indole (4.14 g).

The 3-methylindole derivative from above (3.80 g, 10.94 mmol) wasdissolved in CCl₄ (200 mL) and N-bromosuccinimide (1.85 g, 10.4 mmol)and dibenzoyl peroxide (5 mg) were added. The mixture was refluxed underirradiation by a sun lamp for 3 h. After cooling and removal ofinsoluble solids by filtration, the solution was concentrated underreduced pressure and the residual yellow oil was purified by flashchromatography (6% EtOAc in hexane) to give the title compound ofexample 41 as a yellowish solid (2.28 g).

Example 42 Racemic1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[2-(5-hydroxy-1H-indol-3-yl)-1-pyridin-2-yl-ethyl]-amide (Entry 11032,Table 11)

The procedure of example 39 was followed using 2-(aminomethyl)pyridineas starting material. Alkylation of the benzaldehyde imine derived fromthis compound with the bromomethyltryptophan derivative of example 41gave after removal of Boc protecting groups the racemic amine as thedihydrochloride salt. The crude amine was coupled under usual conditionsto the carboxylic acid derivative of example 2 to give the titlecompound of example 42 after purification by preparative C18reversed-phase HPLC.

Example 43 Racemic1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[12-(5-hydroxy-1H-indol-3-yl)-1-pyridin-4-yl-ethyl]-amide (Entry 11033,Table 11)

Following the above procedure for example 42, but starting with4-(aminomethyl)pyridine, the title compound of example 43 was obtained.

Example 44 (S)-5-Hydroxytryptophan amide

(S)-5-Hydroxytryptophan methyl ester hydrochloride (0.247 g, 0.91 mmol)was stirred overnight at room temperature in ammonium hydroxide (10 mL).After removal of volatiles under vacuum, the title compound of example44 was obtained as a dark solid.

Example 45 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-carbamoyl-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide (Entry 13001,Table 13)

The tryptophan amide derivative of example 44 was coupled in the usualmanner with the carboxylic acid of example 2 to give after purificationby preparative C18 reversed-phase HPLC the title compound of example 45.

Example 462-[4-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-phenoxy]-2-methyl-propionicacid (Entry 1171, Table 1)

Tyrosine amide derivative (entry 16021, Table 16, BILB1028BS) (0.035 g,0.074 mmol) was dissolved in acetone (0.5 mL). Cesium carbonate (0.072g, 0.22 mmol) and tertbutylbromoacetate (0.050 g, 0.22 mmol) were addedand the mixture stirred at 60° C. for 1.5 h. Additional bromoacetate wasadded and the reaction brought to completion (HPLC) by refluxingovernight. The reaction mixture was concentrated under reduced pressureand the residue treated with TFA (1 mL) for 1 h. The product wasisolated directly by preparative C18 reversed-phase HPLC to give thetitle compound of example 46.

Example 47(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-nitro-1H-indol-3-yl)-propionicacid (Entry 1125, Table 1)

(S)-5-Nitrotryptophan methyl ester hydrochloride was prepared followingadapted procedures of T. Hino et al. (Chem. Pharm. Bull. 1983, 1856) andK. Irie et al. (Chem. Pharm. Bull. 1984, 2126). The amino esterderivative was coupled to the carboxylic acid of example 2 in the usualmanner. Following saponification and purification by preparative C18reversed-phase HPLC, the title compound of example 47 was obtained.

Example 48(S)-3-(5-Amino-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 11023, Table 11)

The 5-nitrotryptophan methyl ester intermediate of example 47 (0.400 g,0.72 mmol) was dissolved in DMF (3 mL). Water (0.1 mL) and tindichloride dihydrate (0.812 g, 3.6 mmol) were added and the mixtureheated at 60° C. for 3 h and stirred overnight at room temperature. Thereaction mixture was diluted with water (50 mL), saturated aqueousNaHCO₃ (20 mL) and EtOAc (50 mL). The mixture was vigorously stirred for5 min and filtered to remove solids (wash cake with 50 mL of EtOAc). Theorganic layer from the filtrate was washed with water (3×50 mL) andbrine (50 mL), and subsequently dried over MgSO₄. Volatiles were removedunder reduced pressure and the residue was triturated with TBME (10 mL)to give the 5-aminotryptophan methyl ester derivative as a white solid(0.250 g).

Following saponification and purification by preparative C18reversed-phase HPLC, the title compound of example 48 (W=H) wasobtained.

Example 49(S)-3-{5-[(1-Carboxy-methanoyl)-amino]-1H-indol-3-yl}-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 11024, Table 11, W=COCOOH in Example 48)

The 5-aminotryptophan methyl ester intermediate of example 48 (0.025 g,0.048 mmol) was dissolved in DCM (1 mL) and DIEA (17 μL, 0.095 mmol) andoxalyl methyl chloride (5 μL, 0.053 mmol) were added. The mixture wasstirred for 30 min and volatiles removed under reduced pressure. Theresidue was dissolved in DMSO (0.5 mL), 2.5 N NaOH (0.2 mL) was addedand the mixture stirred at room temperature for 30 min. Afteracidification with TFA, the title compound of example 49 was isolateddirectly by preparative C18 reversed-phase HPLC (0.020 g).

Example 50(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-methanesulfonylamino-1H-indol-3-yl)-propionicacid (Entry 11025, Table 11, W=SO₂CH₃ in Example 48)

Following the procedure described for example 49 and replacing oxalylmethyl chloride by methanesulfonyl chloride, the title compound ofexample 50 was obtained.

Example 51(S)-2-{[1-(Cyclohexyl-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-trifluoromethanesulfonylamino-1H-indol-3-yl)-propionicacid (Entry 11026, Table 11, W=SO₂CF₃ in Example 48)

Following the procedure described for example 49 and replacing oxalylmethyl chloride by trifluoromethanesulfonic anhydride, the titlecompound of example 51 was obtained.

Example 52(S)-2-{[1-(1Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-[5-(2-hydroxy-3,4-dioxo-cyclobut-1-enylamino)-1H-indol-3-yl]-propionicacid (Entry 11027, Table 11, W=Squaric Acid in Example 48)

The 5-aminotryptophan methyl ester intermediate of example 48 (0.050 g,0.095 mmol) was dissolved in MeOH (2 mL) and3,4-dimethoxy-3-cyclobutene-1,2-dione (0.041 g, 0.28 mmol) was added.The mixture was stirred overnight at room temperature. Volatiles werethen removed under reduced pressure and the protected derivativeisolated by preparative C18 reversed-phase HPLC as a yellow solid. Thematerial was dissolved in DMSO (0.5 mL) and treated with 2.5 N NaOH (0.2mL) at room temperature for 30 min. Following acidification with TFA,the title compound of example 52 was isolated by preparative C18reversed-phase HPLC (11 mg).

Example 53 (S)-5-Nitrotryptophan amide hydrochloride

(S)-5-Nitrotryptophan methyl ester hydrochloride (see example 47) wasconverted to the corresponding amide derivative following the proceduredescribed in example 44 for the 5-hydroxy derivative. The amino amidewas then converted to its hydrochloride salt using 4N HCl in dioxane.

Example 54 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-amino-1H-indol-3-yl)-1-carbamoyl-ethyl]-amide (Entry 13005,Table 13)

The 5-nitrotryptophan amide derivative of example 53 was coupled to thecarboxylic acid of example 2 in the usual manner. The nitro group wasthen reduced to the corresponding amine using SnCl₂ dihydrate asdescribed in example 48, to give the title compound of example 54 afterpurification by preparative C18 reversed-phase HPLC.

Example 55 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-carbamoyl-2-(5-methanesulfonylamino-1H-indol-3-yl)-ethyl]-amide(Entry 13006, Table 13)

The 5-aminotryptophan derivative of example 54 was treated withmethanesulfonyl chloride as described for example 50, to give the titlecompound of example 55.

Example 56 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-carbamoyl-2-(5-trifluoromethanesulfonylamino-1H-indol-3-yl)-ethyl]-amide(Entry 13007, Table 13)

The 5-aminotryptophan derivative of example 54 was treated withtrifluoromethanesulfonic anhydride as described for example 51, to givethe title compound of example 56.

Example 57N-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indol-5-yl]-oxalamicacid (Entry 13008, Table 13)

The 5-aminotryptophan derivative of example 54 was treated with methyloxalyl chloride as described for example 49, to give the title compoundof example 57.

Example 58N-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indol-5-yl]-oxalamide(Entry 13009, Table 13, W=H)

The 5-aminotryptophan derivative of example 54 was treated with methyloxalyl chloride as described for example 49. The resulting methyl esterderivative was dissolved in MeOH and treated with excess aqueousammonium hydroxide to give after isolation by preparative C18reversed-phase HPLC the title compound of example 58.

Example 59N¹-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indol-5-yl]-N²-methyl-oxalamide(Entry 13010, Table 13, W=CH₃ in Example 58)

The procedure of example 58 was followed except that methylamine (2M inTHF) was used instead of ammonium hydroxide, to give the title compoundof example 59.

Example 60N¹-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indol-5-yl]-N²-hydroxy-oxalamide(Entry 13011, Table 13, W=OH in Example 58)

The procedure of example 58 was followed except that hydroxylaminehydrochloride and two equivalents of DIEA were used instead of ammoniumhydroxide, to give the title compound of example 60.

Example 614-[({1-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1H-indol-5-ylcarbamoyl]-methanoyl}-amino)-methyl]-benzoicacid (Entry 13012, Table 13, W=CH₂C₆H₄-(4-COOH) in Example 58)

The procedure of example 58 was followed except that4-(aminomethyl)benzoic acid and two equivalents of DIEA were usedinstead of ammonium hydroxide, to give the title compound of example 61.

Example 62 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid{(S)-1-carbamoyl-2-[5-(2-hydroxy-3,4-dioxo-cyclobut-1-enylamino)-1H-indol-3-yl]-ethyl}-amide(Entry 13004, Table 13)

Following the procedure described in example 52, the 5-aminotryptophanderivative of example 54 was converted to the title compound of example62.

Example 63 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-carbamoyl-2-(5-ureido-1H-indol-3-yl)-ethyl]-amide (Entry 13013,Table 13)

The 5-aminotryptophan derivative of example 54 (0.040 g, 0.078 mmol) andKOCN (0.019 g, 0.24 mmol) were dissolved in AcOH (2 mL) and the mixturewas stirred for 1 h at room temperature. The urea derivative of example63 was isolated directly by preparative C18 reversed-phase HPLC.

Example 64 Carbonic acid4-[(S)-2-tert-butoxycarbonylamino-2-(2-methylamino-thiazol-4-yl)-ethyl]-phenylester tert-butyl ester

N,O-BisBoc-(S)-tyrosine

To a mechanically stirred suspension of L-tyrosine (50.00 g, 276 mmol)in 700 mL of water was added di-tert-butyldicarbonate (163.00 g, 745mmol) dissolved in 400 mL of isopropanol. The pH was adjusted to 12.0 byadding a solution of 8N KOH and was subsequently maintained at thisvalue by adding small volumes of the basic solution. After 4 h,di-tert-butyldicarbonate (100 g) was added and the mixture stirredovernight. The isopropanol was evaporated under reduced pressure, theresidue diluted with 1 L of water, washed with Et₂O (500 mL) and a 1:1mixture of Et₂O/hexane (2×500 mL). The aqueous solution was stirred withEt₂O (1 L), cooled in an ice bath and the pH was adjusted to 2.5 withconc. HCl. The organic layer was decanted, the aqueous layerre-extracted with Et₂O (2×500 mL), the organic fractions were pooled,washed with brine (500 mL), dried (MgSO₄) and the solvent evaporated toyield 96.85 g (92%) of a thick clear oil which crystallized on standing.

Carbonic acid4-((S)-2-tert-butoxycarbonylamino-4-diazo-3-oxo-butyl)-phenyl estertert-butyl ester

N,O-Bis-Boc-(S)-tyrosine (6.00 g, 15.73 mmol) was dissolved in THF (40mL), the solution stirred under an argon atmosphere and cooled in an icebath. Isobutyl chloroformate (3.0 6mL, 23.59 mmol) was added followed byDIEA (8.22 mL, 47.19 mmol). Additional isobutyl chloroformate (1 mL) wasadded after 1.5 and 2.5 h. To the cold suspension was then added a ca0.6M Et₂O solution of diazomethane (80 mL) by portions. After 15 min. ofstirring, nitrogen was diffused in the solution for 0.5 hr. The solventwas evaporated, the residue taken into EtOAc (75 ml) and the solutionwashed with 0.5M aqueous citric acid (2×50 mL), 5% aqueous sodiumbicarbonate (2×50 mL) and brine (50 mL). After drying (MgSO₄) andevaporation of the solvent under reduced pressure, the residue waspurified by flash chromatography (20% EtOAc/hexane) to give the titlecompound (5.52 g) of a yellowish solid.

Carbonic acid4-((S)4-bromo-2-tert-butoxycarbonylamino-3-oxo-butyl)-phenyl estertert-butyl ester

The diazoketone prepared above was dissolved in EtOAc (25 mL), thesolution stirred under an argon atmosphere and cooled to −25° C. Asolution of HBr in AcOH (45% w/v, 1.33 mL, 7.40 mmol) was then added insmall portions over 20 min. After 10 min the suspension was diluted withEtOAc (50 mL), washed with 5% aqueous sodium bicarbonate (4×50 mL) andbrine (50 mL). After drying (MgSO₄) and evaporation of the solvent, thetitle compound (2.75 g) was obtained as a clear oil which crystallizedon standing.

Carbonic acid4-[(S)-2-tert-butoxycarbonylamino-2-(2-methylamino-thiazol-4-yl)ethyl]-phenylester tert-butyl ester

To the bromoketone prepared above (0.750 g, 1.64 mmol) dissolved in MeCN(10 mL) was added N-methylthiourea (0.192 g, 2.13 mmol) and the mixturewas stirred 18 h at room temperature. The solvent was evaporated to givethe title compound (0.855 g, >100% yield) as a tan solid that was useddirectly for coupling to the carboxylic acid of example 2 (see example69).

Example 65 Carbonic acid4-[(S)-2-tert-butoxycarbonylamino-2-(2-dimethylamino-thiazol-4-yl)-ethyl]-phenylester tert-butyl ester

Prepared as described in example 64 except that N,N-dimethylthiourea wasused instead of N-methylthiourea.

Example 66 Carbonic acid4-[(S)-2-(2-acetylamino-thiazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-phenylester tert-butyl ester

Prepared as described in example 64 except that N-acetyl-2-thiourea wasused instead of N-methylthiourea.

Example 67 Carbonic acid4-[(S)-2-(2-acetylamino-1H-imidazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-phenylester tert-butyl ester

Prepared as described in example 64 except that 1-acetylguanidine wasused instead of N-methylthiourea.

Example 68 Carbonic acid4-((S)-2-tert-butoxycarbonylamino-2-thiazol-4-yl-ethyl)-phenyl estertert-butyl ester

To a stirred suspension of P₂S₅ (0.89 g, 2.0 mmol) in dry dioxane (5 mL)was added dry formamide (433 μL, 10.9 mmol). The mixture was heated at90° C. for 2.5 h (to maintain a free suspension occasional triturationwas needed). The suspension was allowed to cool to RT, the solidfiltered off and the bromoketone from example 64 (0.229 g, 0.5 mmol) wasadded to the filtrate. The solution was heated to 80° C. for 2 h thendiluted with EtOAC (25 mL), washed with 5% aqueous citric acid (2×20mL), 5% aqueous sodium bicarbonate (2×20 mL) and brine. After drying(MgSO₄) and removal of the solvent under reduced pressure, the titlecompound (186 g) was obtained as a brown solid.

Example 69 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(4-hydroxy-phenyl)-1-(2-methylamino-thiazol-4-yl)-ethyl]-amide(Entry 1240, Table 1)

The crude protected aminothiazole derivative of example 69 (0.075 g,0.17 mmol) was dissolved in dioxane (1 mL) and a 4N solution of HCl indioxane was added. After 2.5 h the solvent was evaporated and theresidue dried under high vacuum for 0.5 h. The resulting hydrochloridesalt was coupled to the carboxylic acid of example 2 in the usual mannerto give the title compound of example 69 after purification bypreparative C18 reversed-phase HPLC.

Example 70 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-dimethylamino-thiazol-4-yl)-2-(4-hydroxyphenyl)-ethyl]-amide(Entry 1241, Table 1)

Prepared as described in example 69 from the aminothiazole derivative ofexample 65.

Example 71 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-acetylamino-thiazol-4-yl)-2-(4-hydroxy-phenyl)-ethyl]-amide(Entry 1242, Table 1)

Prepared as described in example 69 from the aminothiazole derivative ofexample 66.

Example 72 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-acetylamino-1H-imidazol-4-yl)-2-(4-hydroxyphenyl)-ethyl]-amide(Entry 1243, Table 1)

Prepared as described in example 69 from the imidazole derivative ofexample 67.

Example 73 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(4-hydroxy-phenyl)-1-thiazol-4yl-ethyl]-amide (Entry 1250, Table1)

Prepared as described in example 69 from the aminothiazole derivative ofexample 68.

Example 74 Acetic acid4-[(S)-2-(2-amino-thiazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-phenylester

Acetic acid4-((S)-2-tert-butoxycarbonylamino-4-diazo-3-oxo-butyl)-phenyl ester

A solution of Boc-(S)-Tyr(OAc)-OH (1.75 g, 5.4 mmol) in THF (20 mL) wasstirred under argon and cooled to −5° C. DIEA (2.83 mL, 16.2 mmol) andisobutyl chloroformate (1.05 mL, 8.2 mmol) were added. After 1 h,additional isobutyl chloroformate (1 mL) was added and stirringcontinued for 1 h. To the cold suspension was then added an excess of aca 0.6M Et₂O solution of diazomethane (25 mL) in small portions. After16 h of stirring nitrogen was diffused in the solution for 0.5 h. Thesolvent was evaporated, the residue taken in EtOAC (50 ml) and thesolution washed with 0.5M aqueous citric acid (2×25 mL), 5% aqueoussodium bicarbonate (2×25 mL) and brine (25 mL). After drying (MgSO₄) andremoval of the solvent, the residue was purified by flash chromatography(gradient 30 to 50% EtOAC/hexane) to yield 1.14 g (60%) of a yellowishsolid.

Acetic acid4-((S)-4-bromo-2-tert-butoxycarbonylamino-3-oxo-butyl)-phenyl ester

The title compound was prepared as in example 64 using thediazomethylketone from above.

Acetic acid4-[(S)-2-(2-amino-thiazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-phenylester

The bromoketone from above (0.600 g, 1.50 mmol) and thiourea (0.135 g,1.80 mmol) were stirred at room temperature in MeCN (10 mL) for 18 hrs.The solid was filtered and dried under high vacuum to yield the titlecompound.

Example 75 Acetic acid4-[(S)-2-tert-butoxycarbonylamino-2-(2-methyl-thiazol4-yl)-ethyl]-phenylester

Prepared as described in example 74 except that thioacetamide was usedinstead of thiourea, and refluxing conditions were used for condensationwith the bromomethyl ketone. Under those conditions, the N-Bocprotecting group was cleaved. The crude reaction product was thusre-protected (di-tert-butyldicarbonate/aqueous 5% NaHCO₃/dioxane) toallow purification by flash chromatography.

Example 76 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-amino-thiazol-4-yl)-2-(4-hydroxy-phenyl)-ethyl]-amide (Entry16060, Table 16)

The protected aminothiazole derivative of example 74 was deprotected onnitrogen by stirring with 4N HCl-dioxane as in example 69. The resultinghydrochloride salt was coupled to the carboxylic acid of example 2 inthe usual manner to give, after removal of the O-acetyl protecting group(NaOH) the title compound of example 75 after purification bypreparative C18 reversed-phase HPLC.

Example 77 1-Cyclohexyl-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(4-hydroxy-phenyl)-1-(2-methyl-thiazol-4-yl)-ethyl]-amide (Entry1187, Table 1)

Prepared as described in example 76 except that the thiazole derivativeof example 75 was used.

Example 78 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-ethyl]-amide(Entry 1298, Table 1)

Carbonic acid4-((S)-2-tert-butoxycarbonylamino-2-carbamoyl-ethyl)-phenyl estertert-butyl ester

N,O-Bis-Boc-(S)-tyrosine from example 64 (5.00 g, 13.11 mmol) wasdissolved in THF (20 mL), the solution stirred under an argon atmosphereand cooled in an ice bath. DIEA (5.70 mL, 32.7 mmol) was added followedby isobutylchloroformate (2.55 mL, 19.6 mmol). After 45 min a solutionof 2M ammonia in isopropanol (39.3 mL, 78.6 mmol) was added and themixture stirred at room temperature for 18 h. The solvent wasevaporated, the residue taken in EtOAC (100 mL), washed with 5% aqueouscitric acid (2×50 mL), 5% aqueous sodium bicarbonate (2×50 mL) andbrine. After drying (MgSO₄) and evaporation of the solvent, the residuewas dissolved in chloroform (15 mL), stirred vigorously and Et₂O (150mL) was added. The suspension was stirred for 20 min. then the solidfiltered and air dried to yield 3.10 g (62%) of the title compound.

Carbonic acid 4-((S)-2-tert-butoxycarbonylamino-2-cyano-ethyl)-phenylester tert-butyl ester

The tyrosine amide from above (2.00 g, 5.3 mmol) was suspended in DCM(20 mL), stirred under argon and DMSO (1 mL) was added. The resultingsolution was cooled to −78° C. and oxalyl chloride (554 μL, 6.31 mmol)was slowly added followed by DIEA (2.75 mL, 15.8 mmol). The mixture wasstirred for 5 h at room temperature, re-cooled to −78° C., more oxalylchloride (750 μL) was added and the mixture stirred at room temperaturefor 18 h. It was then diluted with DCM (20 mL), washed with 1 N HCl(2×20 mL), 5% aqueous sodium bicarbonate (2×20 mL) and brine (20 mL).The solution was dried (MgSO₄) and the solvent evaporated. The residuewas purified by flash chromatography using 10 to 25% EtOAc/hexane toyield 683 mg (36%) of the title compound as an amorphous solid.

Carbonic acid4-[(S)-2-tert-butoxycarbonylamino-2-(N-hydroxycarbamimidoyl)-ethyl]-phenylester tert-butyl ester

The nitrile prepared above (0.336 g, 0.93 mmol) was dissolved in MeOH (3mL), hydroxylamine hydrochloride (0.070 g, 1.02 mmol) was added followedby sodium bicarbonate (0.156 g, 1.85 mmol). The mixture was stirred 18 hunder an argon atmosphere. The solvent was evaporated, the residue takenup in EtOAc (25 mL), washed with 5% aqueous sodium bicarbonate and brine(20 mL) The solution was dried (MgSO₄) and the solvent evaporated toyield 353 mg (96%) of the title compound.

Carbonic acid4-[(S)-2-tert-butoxycarbonylamino-2-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-ethyl]-phenylester tert-butyl ester

The amidoxime prepared above (0.200 g, 0.51 mmol) was dissolved in THF(400 μL), trifluoroacetic anhydride (216 μL, 1.53 mmol) was addedfollowed by TFA (39 μL, 0.51 mmol). The solution was heated to 70° C.for 2 h, allowed to cool to room temperature, diluted with EtOAc, washedwith 5% aqueous sodium bicarbonate and brine. The solution was dried(MgSO₄) and the solvent evaporated to yield 237 mg (98%) of the titlecompound that was used directly in the next step.

1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-ethyl]-amide(Entry 1298, Table 1)

The protected heterocycle from above was deprotected as described inexample 64 and coupled to the carboxylic acid of example 2 in the usualmanner. The title compound of example 78 was obtained after purificationby preparative C18 reversed-phase HPLC.

Example 79 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-cyano-2-(4-hydroxy-phenyl)-ethyl]-amide (Entry 1170, Table 1)

Acetic acid 4-((S)-2-tert-butoxycarbonylamino-2-carbamoyl-ethyl)-phenylester

To a solution of Boc-tyrosine amide (0.960 g, 3.4 mmol) in pyridine (10mL) stirred under argon was added acetic anhydride (808 μL, 8.56 mmol).After 18 hrs of stirring the solvent was evaporated, the residue takenin EtOAc (30 mL) washed with 5% aqueous citric acid (3×20 mL) and brine.The solution was dried (MgSO₄) and the solvent evaporated to yield 949mg (86%) of the title compound.

Acetic acid 4-((S)-2-tert-butoxycarbonylamino-2-cyano-ethyl)-phenylester

The amide from above was dissolved in a 4/1 mixture of DCM/DMSO, thesolution stirred under an argon atmosphere and cooled to −78° C. Oxalylchloride (65 μL, 0.74 mmol) was added dropwise, the solution stirred for30 min and triethylamine (259 μL, 1.86 mmol) was added. After 1 h at−78° C. the solution was allowed to warm to room temperature and stirredfor 1.5 h. EtOAc (40 mL) was added, the solution washed with 5% aqueoussodium bicarbonate (20 mL) and brine (20 mL). The solution was dried(MgSO₄) and the solvent evaporated. The residue was purified by flashchromatography (gradient 20 to 30% EtOAc/hexane) to yield 115 mg (61%)of the title compound.

1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-cyano-2-(4-hydroxy-phenyl)-ethyl]-amide (Entry 1170, Table 1)

Following the procedure of example 76, the nitrile from above wascoupled to the carboxylic acid of example 2 to give after purificationby preparative C18 reversed-phase HPLC, the title compound of example79.

Example 80(S)-3-(3-Acetyl-4-hydroxy-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-imidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 1147, Table 1)

(S)-3-(3-Acetyl-4-hydroxyphenyl)alanine methyl ester hydrochloride wasprepared according to the method of D. L. Boger et al. (J. Org. Chem.1987, 52, 5283) and coupled to the carboxylic acid of example 2 in theusual manner.

Example 81(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-methanoyl]-amino}-3-[4-hydroxy-3(RS)-(1-hydroxy-ethyl)-phenyl]propionicacid (Entry 16052, Table 16)

An aliquot from the coupling reaction of example 80 was treated withexcess sodium borohydride at room temperature for 1 h. Followingacidification with TFA, the title compound of example 81 was isolated asa mixture of epimers (carbinol center) by prep HPLC.

Example 82(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(4-methyl-2-oxo-2H-1-benzopyran-6-yl)-propionicacid (Entry 1126, Table 1)

(S)-3-(3-Acetyl-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester

To a solution of (S)-3-(3-acetyl-4-hydroxyphenyl)alanine methyl esterhydrochloride (1.50 g, 5.48 mmol), prepared according to the method ofD. L. Boger et al. (J. Org. Chem. 1987, 52, 5283), in DMF (15 mL) wasadded di-tert-butyldicarbonate (1.20 g, 5,48 mmol) and DIEA (1.91 mL,10.96 mmol). The solution was stirred under an argon atmosphere for 16h. It was poured in a 0.5 N solution of KHSO₄ (200 mL), extracted withEtOAc (2×75 mL) and the combined organic solutions were washed withbrine (50 mL). The extract was dried (MgSO₄) and the solvent evaporatedto yield 1.80 g (97%) of the title compound.

(S)-2-tert-Butoxycarbonylamino-3-(4-methyl-2oxo-2H-1-benzopyran-6-yl)-propionicacid methyl ester

To a solution of the above ketone (0.250 g, 0.74 mmol) in benzene (4 mL)was added methyl (triphenylphosphoranylidene)acetate (0.496 g, 1.48mmol). The solution was refluxed for 5 h then evaporated to dryness. Theresidue was purified by flash chromatography (gradient 20 to 35%EtOAc/hexane) to yield 70 mg (26%) of the title compound.

(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(4-methyl-2-oxo-2H-1-benzopyran-6-yl)-propionicacid (Entry 1126, Table 1)

The amino ester derivative from above was deprotected with 4N HCl indioxane and coupled to the carboxylic acid of example 2 in the usualmanner to give after saponification the title compound of example 82.

Example 83(E)-3-[5-((S)-2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-methoxy-phenyl]-acrylicacid (Entry 16051, Table 16)

To a solution of Boc-3′-iodo-L-tyrosine methyl ester (B. Rzeszotarska etal. Liebigs Ann. Chem., 1981, 7,1294-1302) (0.200 g, 0.47 mmol) in DMF(1 mL) was added iodomethane (32 μL, 0.52 mmol) and DIEA (125 μL, 0.71mmol). The solution was stirred at room temperature for 16 h then pouredin water (15 mL) and the product extracted with EtOAc (15 mL). Theorganic solution was evaporated and the residue purified by flashchromatography (gradient 20 to 25% EtOAc/hexane) to yield 127 mg (62%)of the title compound.

A solution of the above iodotyrosine derivative (0.110 g, 0.25 mmol) inMeCN (3 mL) was stirred vigorously and argon was diffused in it for 20min. Methyl acrylate (225 μL, 2.50 mmol), DIEA (132 μL, 0.75 mmol),tri-o-tolylphosphine (11 mg) and palladium acetate (11 mg) were added.Argon diffusion was continued for 5 min then the system was sealed andheated at 80° C. with vigorous stirring for 18 h. After cooling to roomtemperature, argon was diffused again for 20 min, additional palladiumacetate (20 mg) and tri-o-tolylphosphine (20 mg) were added and thesystem sealed and heated at 90° C. for 16 h. The solvent was thenevaporated, the residue taken in EtOAc (20 mL) washed with 1M KHSO₄ (10mL), 5% aqueous sodium bicarbonate (10 mL) and brine (10 mL). Thesolution was dried (MgSO4) and the solvent evaporated. The residue waspurified by flash chromatography (25% EtOAc/hexane) to yield 102 mg(100%) of the title compound.

The above tyrosine fragment was deprotected wit 4N HCl-dioxane andcoupled in the usual manner to the carboxylic acid of example 2.Following saponification of the ester groups the title compound ofexample 83 was isolated by preparative C18 reversed-phase HPLC.

Example 84(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)methanoyl]-amino}-3-[3-(2H-tetrazol-5-yl)-phenyl]-propionicacid (Entry 16057, Table 16)

A suspension of L-3-cyano-phenylalanine (0.150 g, 0.79 mmol), lithiumchloride (0.060 g, 1.43 mmol) and sodium azide (0.067 g, 1.03 mmol) inmethoxyethanol (500 μL) was heated at 125° C. for 18 h. The solvent wasevaporated to yield 370 mg of crude 3-tetrazolyl-L-phenylalanine.

The crude tetrazole prepared above was dissolved in MeOH (20 mL), a 4NHCl in dioxane solution (4 mL) was added and the solution refluxed for 3h. The solution was evaporated to dryness to yield 307 mg of the crudemethyl ester hydrochloride.

The methyl ester from above was coupled to the carboxylic acid ofexample 2 in the usual manner to give after saponification andpurification by preparative C18 reversed-phase HPLC the title compoundof example 84.

Example 85(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-[4-hydroxy-3-(2H-tetrazol-5-yl)-phenyl]-propionicacid (Entry 16056, Table 16)

To a solution of Boc-3′-iodo-L-tyrosine methyl ester (B. Rzeszotarska etal. Liebigs Ann. Chem., 1981, 7,1294-1302) (0.300 g, 0.71 mmol) in DMF(2 mL) were added DIEA (250 μL, 1.43 mmol), and acetic anhydride (80 μL,0.85 mmol). The solution was stirred at room temperature for 2 h thenpoured in a 1M solution of KHSO₄ (40 mL). The mixture was extracted withEtOAc (20 mL) and the organic extract washed with 5% aqueous sodiumbicarbonate and brine. Drying (MgSO₄) and removal of the solvent gavethe acetylated tyrosine derivative (330 mg, >100%).

A solution of the above acetylated iodotyrosine derivative (0.120 g,0.26 mmol) in toluene (5 mL) was stirred vigorously and flushed withargon for 30 min. Then were added2-benzyloxymethyl-5-(tributylstannyl)tetrazole (B. C. Bookser,Tetrahedron Lett., 2000, 41, 2805) (0.149 g, 0.31 mmol),tetrakis(triphenylphosphine) palladium (0) (15 mg, 0.013 mmol) andcopper(I) iodide (5 mg, 0.026 mmol). The system was sealed and heated at110° C. for 18 h. The mixture was cooled to room temperature, a 15%aqueous solution of KF (2 mL) was added and the mixture vigorouslystirred for 45 min. It was filtered over celite and the cake was washedwith EtOAc (4×20 mL). The filtrate was dried (MgSO₄) and the solventevaporated. The residue was purified by flash chromatography (gradient10 to 30% EtOAc/hexane) to yield 54 mg (40%) of the protected3-tetrazolyl-tyrosine derivative.

The tetrazole derivative prepared above was dissolved in MeOH (8 mL) and10% Pd/C (50 mg) was added. The mixture was stirred under one atmosphereof hydrogen gas for 16 h. The suspension was filtered over celite washedwith MeOH, the filtrate was evaporated and the residue re-dissolved inMeOH (20 mL). It was then hydrogenated at 50 psi with palladium acetate(100 mg) on a Parr shaker for 18 h. After filtration over celite,washing and evaporation of the filtrate 32 mg (93%) of the deprotectedtetrazole derivative were obtained.

The N-Boc derivative from above was deprotected with 4 N HCl-dioxane andcoupled in the usual manner to the carboxylic acid of example 2.Following removal of ester groups by saponification, the title compoundof example 85 was isolated by preparative C18 reversed-phase HPLC.

Example 86 Carbonic acid3-[(S)-2-tert-butoxycarbonylamino-2-(2-methylamino-thiazol-4-yl)-ethyl]-1H-indol-5-ylester tert-butyl ester

(S)-5-Hydroxytryptophan was converted to the bis-Boc derivative by themethod of V. F. Pozdnev, Chem. Nat. Compd. (Engl. Transl.) 1982, 18 (1),125) which was isolated as the free carboxylic acid. This material(1.0377 g, 2.47 mmol) was dissolved in THF (5 mL), DIEA (0.645 mL, 3.7mmol) was added and the mixture cooled in ice. Isobutyl chloroformate(0.384 mL, 2.96 mmol) was added and the mixture stirred at 0-5° C. for18 h. Excess diazomethane in Et₂O (0.6 M, 15 mL) was then added and themixture stirred for 1 h. Another portion of diazomethane (10 mL) wasadded and after 40 min, the reaction was diluted with Et₂O (75 mL). Thesolution was washed successively with 10% aqueous citric acid (25 mL)and saturated aqueous NaHCO₃ (25 mL), and dried (MgSO₄). Volatiles wereremoved under reduced pressure and the residue purified by flashchromatography with 40% EtOAc hexane. The diazomethylketone was obtainedas a yellow foam (0.783 g).

The diazomethylketone from above was dissolved in EtOAc (10 mL) and thesolution cooled to −30° C. A solution of HBr in AcOH (48% w/w, 0.384 mL)was added dropwise over 60 min. The cold reaction mixture was thendiluted with Et₂O (100 mL) and washed successively with 10% aqueouscitric acid (2×25 mL) and saturated aqueous NaHCO₃ (25 mL), and dried(MgSO₄). Volatiles were removed under reduced pressure and the residuecoevaporated with hexane to give the bromomethylketone as a white foam(0.870 g). The bromomethylketone from above was reacted withN-methylthiourea as described for example 63.

Example 87 Carbonic acid3-[(S)-2-tert-butoxycarbonylamino-2-(2-dimethylamino-thiazol-4-yl)-ethyl]-1H-indol-5-ylester tert-butyl ester

The bromomethylketone of example 86 was reacted withN,N-dimethylthiourea as described for example 64.

Example 88 Carbonic acid3-[(S)-2-(2-acetylamino-thiazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-1H-indol-5-ylester tert-butyl ester

The bromomethylketone of example 86 was reacted with N-acetyl-2-thioureaas described for example 63.

Example 89 Carbonic acid3-((S)-2-tert-butoxycarbonylamino-2-thiazol-4-yl-ethyl)-1H-indol-5-ylester tert-butyl ester

The bromomethylketone of example 86 was converted to the thiazoleheterocycle as described for example 68.

Example 90 Carbonic acid3-[(S)-2-tert-butoxycarbonylamino-2-(2-methyl-thiazol-4-yl)-ethyl]-1H-indol-5-ylester tert-butyl ester

The bromomethylketone of example 86 (0.423 g, 0.85 mmol) was reactedwith thioacetamide (0.128 g, 1.70 mmol) in MeCN (5 mL) at roomtemperature for 18 h. The solvent was then removed under reducedpressure and the residue dissolved in DMSO (1.5 mL). This solution wasadded dropwise with stirring to a mixture of water (15 mL) and DIEA (0.2mL). The precipitate that formed was collected by filtration, washedwith water and dried to give the title compound of example 90 (0.383 g).

Example 91 Carbonic acid3-[(S)-2-(2-amino-thiazol-4-yl)-2-tert-butoxycarbonylamino-ethyl]-1H-indol-5-ylester tert-butyl ester

Prepared as described for example 90, except that thiourea was usedinstead of thioacetamide.

Example 92 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(2-methyl-thiazol-4-yl)-ethyl]-amide(Entry 14001, Table 14)

The Bis-Boc thiazole fragment of example 90 was deprotected using 4 NHCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 92 was isolated by preparative C18 reversed-phase HPLC.

Example 93 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-amino-thiazol-4- yl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 14002, Table 14)

The Bis-Boc aminothiazole fragment of example 91 was deprotected using 4N HCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 93 was isolated by preparative C18 reversed-phase HPLC.

Example 94 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(2-methylamino-thiazol-4-yl)-ethyl]-amide(Entry 14004, Table 14)

The Bis-Boc aminothiazole fragment of example 86 was deprotected using 4N HCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 93 was isolated by preparative C18 reversed-phase HPLC.

Example 95 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-dimethylamino-thiazol-4-yl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13005 Table 14)

The BisBoc aminothiazole fragment of example 87 was deprotected using 4N HCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 94 was isolated by preparative C18 reversed phase HPLC.

Example 96 1-Cyclohexyl-2furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-acetylamino-thiazol-4-yl)-2-(5-hydroxyl-1-indol-3-yl)-ethyl]-amide(Entry 14006, Table 14)

The Bis-Boc aminothiazole fragment of example 88 was deprotected using 4N HCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 96 was isolated by preparative C18 reversed-phase HPLC.

Example 97 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-H-indol-3-yl)-1-thiazol-4-yl-ethyl]-amide (Entry14007, Table 14)

The Bis-Boc thiazole fragment of example 89 was deprotected using 4 NHCl-dioxane and the resulting hydrochloride salt was coupled in theusual manner to the carboxylic acid of example 2. The title compound ofexample 97 was isolated by preparative C18 reversed-phase HPLC.

Example 98[4-((S)-4-Bromo-2-tert-butoxycarbonylamino-3-oxo-butyl)-phenoxy]-aceticacid methyl ester

The para-toluenesulfonic acid salt of tyrosine benzyl ester (5.05 g,11.4 mmol) was dissolved in THF (50 mL) containing DIEA (2.18 mL, 12.5mmol) and di-tert-butyldicarbonate (2.98 g, 13.7 mmol) was added in oneportion. The reaction was stirred 1.5 h at room temperature. Volatileswere removed under reduced pressure and the residue was dissolved inEt₂O (150 mL). The solution was washed successively with water (25 mL),5% citric acid (25 mL) and 5% NaHCO₃ (25 mL).

After drying (MgSO₄), the solvent was evaporated under reduced pressureand the residue dissolved in acetone (100 mL). Cesium carbonate (4.83 g,14.8 mmol) and methyl bromoacetate (1.3 mL, 13.7 mmol) were added andthe heterogeneous mixture was stirred overnight at room temperature.Solids were then removed by filtration (acetone for washings) and thefiltrate evaporated. The residue was dissolved in Et₂O (150 mL) andwashed with water (25 mL) and brine (25 mL). After drying (MgSO₄), thesolution was concentrated and the residue purified by flashchromatography using 25-50% EtOAc/hexane as eluent. The fully protectedtyrosine derivative was obtained as a colorless oil (3.61 g).

The benzyl ester from above (3.60 g, 8.1 mmol) was dissolved in EtOAc(25 mL) and hydrogenated (1 atm H₂ gas) over 20% Pd(OH)₂/C (350 mg) for2.5 h. The catalyst was removed by filtration and the solvent removedunder reduced pressure to give the free acid derivative as a colorlessoil (3.19 g).

The tyrosine derivative from above (1.20 g, 3.4 mmol) was dissolved inTHF (15 mL) and the solution cooled to −20° C. N-Methylmorpholine (0.45mL, 4.1 mmol) was added followed by isobutylchloroformate (0.48 mL, 3.74mmol). The mixture was stirred at −20° C. for 30 min. Diazomethane inEt₂O (0.6 M, excess) was added and the solution stirred for 30 min atroom temperature. A second portion of diazomethane was added andstirring resumed for an additional 30 min (complete by TLC and HPLC).The reaction mixture was diluted with Et₂O (100 mL) and the solutionwashed successively with water (2×25 mL), 5% NaHCO₃ (25 mL) and brine(25 mL). The extract was dried (MgSO₄) and concentrated to give thedesired diazomethylketone as a yellow oil (1.26 g).

The diazomethylketone from above (1.10 g, 3.4 mmol) was dissolved inEtOAc (10 mL) and the solution cooled to 0° C. A solution of HBr in AcOH(48% w/w, 0.44 mL, 3.4 mmol) was added dropwise over 5 min, followed byan additional portion (0.22 mL, 1.7 mmol). After stirring for 10 min,the reaction mixture was diluted with Et₂O (150 mL) and washedsuccessively with water (25 mL), 10% citric acid (25 mL) and 5% NaHCO₃(2×25 mL). After drying (MgSO₄), the solvent was evaporated underreduced pressure to give the desired bromomethylketone as a light yellowsolid (1.14 g).

Example 99{4-[(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-2-(2-methyl-thiazol-4-yl)-ethyl]-phenoxy}-aceticacid (Entry 1131, Table 1, R=CH₃)

Following the procedure of example 90, the bromoketone of example 98 wasreacted with thioacetamide. Following removal of the Boc protectinggroup (if necessary) with 4N HCl in dioxane, the amine hydrochloridesalt was coupled to the carboxylic acid of example 2 in the usualmanner. The ester protecting group was then removed by saponification(NaOH) and the final product isolated by preparative C18 reversed-phaseHPLC.

Example 100[4-((S)-2-(2-Amino-thiazol-4-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-phenoxy]-aceticacid (Entry 19002 Table 19, R=NH₂ in example 99)

Following the procedure of example 99 but replacing the thioacetamide bythiourea, the title compound of example 100 was obtained.

Example 101{4-[(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-2-(2-isopropylamino-thiazol-4-yl)-ethyl]-phenoxy}-aceticacid (Entry 1133, Table 1, R=NH¹Pr in example 99)

Following the procedure of example 99 but replacing the thioacetamide byN-isopropyl-2-thiourea, the title compound of example 101 was obtained.

Example 102[4-((S)-2-(2-Acetylamino-thiazol-4-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-phenoxy]-aceticacid (Entry 1134, Table 1, R=NHAc in example 99)

Following the procedure of example 99 but replacing the thioacetamide byN-acetyl-2-thiourea, the title compound of example 102 was obtained.

Example 103{4-[(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-2-(2-methylamino-thiazol-4-yl)-ethyl]-phenoxy}-aceticacid (Entry 1140, Table 1, R=NHMe in example 99)

Following the procedure of example 99 but replacing the thioacetamide byN-methyl-2-thiourea, the title compound of example 103 was obtained.

Example 104{4-[(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-2-(2-dimethylamino-thiazol-4-yl)-ethyl]-phenoxy}-aceticacid (Entry 1141, Table 1, R=N(CH₃)₂ in example 99)

Following the procedure of example 99 but replacing the thioacetamide byN,N-dimethyl-2-thiourea, the title compound of example 104 was obtained.

Example 105[4-((S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-2-thiazol-4-yl-ethyl)-phenoxy]-aceticacid (Entry 1150, Table 1, R=H in example 99)

Following the procedure of example 68, the title compound of example 104was obtained.

Example 106 Solid Phase Synthesis of Inhibitors, Wherein, X=CH, Y=O,Z=OH, n=0

To a solution of the 4-fluoro-3-nitrobenzoic acid (0.12 mol, 22.2 g) in100 mL of anhydrous DCM was added 10 drops of anhydrous DMF. To thissolution was added dropwise over 60 min, oxalyl chloride (0.144 mol,12.6 mL). During the addition, the solid slowly dissolved to give riseto a yellow solution. The mixture was stirred for an additional 4 h andthe solvent was stripped down to give a yellow oil. This oil wasdistilled under vacuum (110° C., 1.5 mm Hg) to give4-fluoro-3-nitrobenzoyl chloride as a light yellow liquid (22.0 g, 90%yield).

On a solid phase synthesizer (Advanced Chemtech ACT 90), Wang resin(Nova Biochem, loading: 1.2 mmol/g, 20 mmol, 16.7 g) was washed twicewith DCM (100 mL), twice with i-PrOH (100 mL) and was dried overnightunder high vacuum over P₂O₅. The following day, the resin was washedwith anhydrous DCM (2×100 mL) and was suspended in anhydrous DCM (100mL). To the suspension was added DIEA (30 mmol, 5.2 mL) followed by asolution of 4-fluoro-3-nitrobenzoyl chloride (22 mmol, 4.48 g) dissolvedin 10 ml of anhydrous DCM. The slurry was shaken for 3 h, the solutionwas drained and the resin was washed twice with 100 mL-portions ofanhydrous DCM. The resin was then suspended in anhydrous DCM (100 mL)and was treated with DIEA (30 mmol, 5.2 mL) followed by acetic anhydride(24 mmol, 2.3 mL). After shaking for 2 h, the solution was drained andthe resin was washed successively with DCM (2×100 mL), i-PrOH (2×100mL), DCM (2×100 mL) and finally with i-PrOH (3×100 mL). The resin wasdried overnight under high vacuum. To calculate the level ofincorporation, the resin (45.9 mg) was treated with a 1:1 mixture ofTFA/1,2-dichloroethane (1.5 mL) for 1 h. The resin was filtered and waswashed twice with 1,2-dichloroethane (1.5 mL). The filtrates werecombined and concentrated under vacuum. The residue was lyophilized fromMeCN/H₂O to give 4-fluoro-3-nitro benzoic acid as a yellow solid (6.3mg, 0.033 mmol). Based on recovered compound, the loading was calculatedto be 0.74 mmol/g.

The following steps were performed on a solid-phase synthesizer (ACT 496from Advanced Chemtech), using the 96-well reaction block:

Amine Addition

Each well was filled with the benzoic acid resin from above (0.03 mmol,40 mg) and was washed with DMF (3×1.2 mL) and DMSO (2×1.2 mL). To eachwell was added DMSO (530 μL), a 1 M solution of the amine R₂—NH₂ (600μL, 0.6 mmol) and DIEA (0.4 mmol, 70 μL). The resins were shaken for 15h at room temperature and the solvent was drained. The resins werewashed successfully with 1.2-mL portions of DMF (3×), MeOH (3×), and DMF(4×).

Reduction of the Nitro Group

The resins were then suspended in DMF (600 μL) and were shaken with a 1M solution of SnCl₂.2 H₂O (600 μL, 0.6 mmol) for 25 h. The solvent wasdrained, the resins were washed successively with 1.2-mL portions of 1:1DMF-H₂O (4×), DMF (4×), MeOH (4×) and NMP (4×).

Formation of the Benzimidazole Ring

Each resin was suspended in DMF (200 μL) and a 1 M solution of thealdehyde in DMF was added (0.20 mmol, 200 μL), followed by a 0.25 Msolution of chloranil in NMP (0.20 mmol, 800 μL). The resins were shakenfor 18 h, the liquid was drained and the resins were washed successivelywith 1.2-mL portions of NMP (3×), 1 M DIEA/NMP (2×), NMP (3×), MeOH (3×)and DCM (4×). The reaction block was placed in a vacuum chamber for 30min in order to dry the resin.

Cleavage from the Resin

In each well was added 1.0 mL of a 1:1 solution ofTFA/1,2-dichloroethane and the resins were shaken for 1 h. The wellswere drained and the resins washed once with 1.0 mL of the cleavagesolution. Volatiles were evaporated in a vacuum centrifuge to give thecrude benzimidazole 5-carboxylic acids in which X=CH, Y=O, Z=OH and n=0.

Example 107 (Entries 2110, 2111, 2112, 2114-2117, 2120-2123, 2125-2128,2139-2143, Table 2)

The following steps were performed on a solid-phase synthesizer (ACT 496from Advanced Chemtech), using the 96-well reaction block.

The starting diamine resin was prepared as described in example 106.Each well was filled with resin (0.0203 mmol, 35 mg) and was washed withDMF (3×1.2 mL). To each well was added a 0.5 M solution of DIEA in DMF(200 μL, 0.1 mmol), a 0.2 M solution of the acid R₁—CO₂H in DMSO (500μL, 0.1 mmol) and a 0.2 M solution of HATU in DMF (500 μL, 0.1 mmol).The resins were shaken for 6 h at room temperature and the solvent wasdrained. The coupling was repeated for another 6 h with fresh reagent.The resins were washed successfully with 1.2-mL portions of DMF (3×),MeOH (3×), and DCM (3×).

Cleavage from the Resin

In each well was added 1.0 mL of a 30% solution ofTFA/1,2-dichloroethane and the resins were shaken for 1.5 h. The wellswere drained and the resins washed once with 2 mL of 1,2-dichloroethane.The resulting filtrates containing 10% TFA in 1,2-dichloroethane washeated at 80° C. for 13 h. The volatiles were removed under vacuum andthe residue was lyophilized from MeCN/H₂O. The crude benzimidazole5-carboxylic acid derivatives thus obtained were coupled with5-(S)-hydroxytryptophan methyl ester hydrochloride, saponified andpurified in the usual manner:

Example 108 (Entries 1157-1169, 1178, 1179, 1236-1239, Table 1)

Note 1: In the case of compound entries 1157, 1158, 1236, 1237, 1238 and1239, the coupling with the y-amino butyryl fragment was omitted.

Note 2: In the case of compound entries 1159 and 1178, the amino acidfragment was coupled directly on the bromo Wang resin and, in the formercase, Fmoc-d,l-alanine was used.

Note 3: In case of compound entries 1236, 1237, 1238, and 1239, thenitroacid was coupled to standard Wang resin using the MSNT method of J.Nielsen and L. O. LyngsØ (Tetrahedron Lett. 1996, 37, 8439).

The following steps were performed on a solid-phase synthesizer (ACT 496from Advanced Chemtech), using the 96-well reaction block:

Anchoring on the Resin

Each well was filled with the bromo Wang resin (0.044 mmol, 40 mg) andwas washed with DMF (3×1.2 mL). To each well was added DMF (200 μL), a 1M solution of DIEA in DMF (300 μL, 0.3 mmol), and each of the nitro acidderivatives (0.176 mmol) dissolved in 500 μL of DMF. The resins wereshaken for 15 h at room temperature and the solvent was drained. Theresins were washed successively with 1.2-mL portions of DMF (3×), MeOH(3×), and DMF (3×).

Reduction of the Nitro Group and Coupling of Fmoc-β-amino Butyric Acid

The nitro group was reduced to the corresponding aniline using tin (II)chloride dihydrate (1.2 mL of a 0.5 M solution in DMF, 0.6 mmol) for 24h followed by washing (3×1.2 mL) with DMF, DMF/H₂O, DMF, MeOH and DMF.The resin was then suspended in DMF (200 μL) and treated with a 0.5 Msolution of DIEA in DMF (300 μL, 0.15 mmol), a 0.13 M solution ofFmoc-d,l-β-aminobutyric acid (500 μL, 0.066 mmol) and a 0.13 M solutionof TBTU in DMF (500 μL, 0.066 mmol). After shaking for 5 h at 60° C.,and since several reactions were not complete as indicated by thecleavage of a few resin beads, fresh reagents were added and a secondcoupling was done using HATU as coupling agent at room temperature for18 h.

Coupling of the Core Benzimidazole and Cleavage from the Resin

The Fmoc group was cleaved with 20% piperidine/DMF (20 min) and afterwashing, the core benzimidazole was coupled under standard conditions tothe carboxylic acid of example 2 using TBTU as coupling agent (roomtemperature, 18 h).

Cleavage from the Resin

In each well was added 1.0 mL of a 50% solution ofTFA/1,2-dichloroethane and the resins were shaken for 1 h. The wellswere drained and the resins washed once with 1 mL of the 50% TFA/1,2-DCEsolution. The volatiles were removed under vacuum and the compounds werepurified by semi-prep reversed phase chromatography.

Example 109 (Entries 1180-1185, Table 1)

The mono-Boc diamines 1-6 were synthesized from the correspondingdiamino compounds according to a literature procedure (see Carceller,E.; Merlos, M.; Giral, M.; Balsa, D.; Garcia-Rafanell, J.; Forn, J. J.Med. Chem. 1996, 39, 487). 3-Aminopiperidine was prepared byhydrogenation of 3-aminopyridine at 45 psi H₂ over 5% w/w Rh/Al₂O₃ for 9days. Coupling of the mono-protected diamino compound to the carboxylicacid of example 2 was performed using HATU. Following removal of thecarbamate protecting group (TFA), the title compounds of example 109were isolated by preparative C18 reversed-phase HPLC:

Example 110 (Entry 1191-1204, 1205-1209, 1210, 1211-1227, 1261-1274, and1275-1292, Table 1)

The following steps were performed on a solid-phase synthesizer (ACT 496from Advanced Chemtech), using the 96-well reaction block.

Reaction with Anhydrides and Isocyanates

In each well of the reaction block was added 0.5 mL of DMF followed by a0.06 M solution of the appropriate amine from example 109 in DMF (0.5mL, 0.03 mmol). In the case of anhydride additions, DIEA was added tothe well (8.7 μL, 0.05 mmol). The isocyanates or anhydrides were addedto the appropriate wells as a 0.45 M solution in DMF (0.10 mL, 0.045mmol).

Anhydrides addition: After shaking 5 h, a 1 M solution of NaOH/H₂O wasadded (0.10 mL, 0.01 mmol) and the mixture was shaken for 14 h.

Isocyanates addition: The mixture was shaken for 19 h.

Work-up: In all the wells was added AcOH (11 μL, 0.2 mmol) and aftershaking for 5 minutes, the solutions were sequentially purified bysemi-Preparative C18 reversed-phase HPLC (20 mm×50 mm YMC column, 5 um,120A) using a water-MeCN gradient containing 0.06% TFA.

Reaction with Aldehydes

In each well of the reaction block was added 0.2 mL oftrimethylorthoformate followed by a 0.345 M solution of each of theappropriate amines from example 109 dissolved in trimethylorthoformate(0.30 mL, 0.115 mmol). Each of the aldehydes was dissolved in a 1% AcOHsolution in trimethylorthoformate to make a 1.15 M solution. Eachaldehyde solution was added to the appropriate well (0.10 mL, 0.115mmol) and the solutions were shaken for 30 minutes. A solution 0.57 M ofsodium cyanoborohydride in trimethylorthoformate was then added in eachwell (0.10 mL, 0.057 mmol) and the mixture was shaken for 3 h afterwhich time, a 0.1 M solution of HCl in water was added (0.10 mL, 0.010mmol). After shaking for 5 minutes, the solutions were filtered into a8-mL vial and the well was washed with 1 mL of MeOH. The volatilesolvents were removed under vacuum and the residue was dissolved in DMSOfor purification by semi-preparative C18 reversed-phase HPLC.

Example 111 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid{(S)-1-(2-amino-thiazol-4-yl)-2-[4-(2H-tetrazol-5-yl)-phenyl]-ethyl}-amide(Entry 16059, Table 16)

4-Cyano-L-phenylalanine (0.500 g, 2.63 mmol) was dissolved in DMF (10mL) and sodium azide (0.342 g, 5. 26 mmol) was added. The mixture waspurged with argon gas and heated in a sealed tube at 100-120° C. for 18h followed by 48 h at room temperature. HCl (1 M, 5 mL) was added andthe mixture evaporated to dryness under vacuum. MeOH (25 mL) was addedfollowed by thionyl chloride (1 mL, 13.7 mmol) and the mixture refluxedfor 3 h. After cooling to room temperature, the solution was filtered toremove insoluble material and the filtrate evaporated to dryness. Theresidue was taken up in MeCN (20 mL), DIEA (2.74 mL, 15.8 mmol) anddi-tert-butyldicarbonate (1.15 g, 5.26 mmol) were added, and the mixturestirred overnight at room temperature. Saturated aqueous NaHCO₃ (6 mL)was added, and after stirring for 1 h at room temperature, the reactionwas quenched with AcOH (3.5 mL). After diluting with water (50 mL), theproduct was extracted into EtOAc (2×50 mL), washed with brine (25 mL)and dried (Na₂SO₄). After evaporation of the solvent, the desiredtetrazole derivative was obtained as a tan-colored solid (0.775 g).

The tetrazole compound from above (0.752 g, 2.16 mmol) was dissolved inTHF (20 mL) and DIEA (0.75 mL, 4.3 mmol) and triphenylchloromethane(trityl chloride, 0.604 g, 2.16 mmol) were added. The reaction wasstirred for 1 h at room temperature and then quenched with 1 N NaOH (13mL, 13 mmol). After stirring overnight at room temperature, the reactionmixture was cooled in ice and acidified to pH 3-4 with 1 N HCl. Theproduct was extracted into EtOAc (50 mL), washed with brine and thesolution dried (Na₂SO₄). Evaporation of the solvent gave a yellowresidue that was purified by passing through a pad of silica gel usingEtOAc as eluent. The product was then dissolved in TBME (5 mL) andhexane (10 mL) was added. The precipitated material was collected byfiltration and dried to give the desired 4-tetrazolyl-L-phenylalaninefree acid as a white solid (0.784 g).

The free carboxylic acid from above (0.278 g, 0.5 mmol) was dissolved inTHF (10 mL) and the solution cooled to −30° C. DIEA (105 μL, 0.6 mmol)was added followed by isobutylchloroformate (72 μL, 0.55 mmol). Themixture was stirred for 30 min and excess diazomethane (0.6 M in Et₂O, 5mL) was added. After stirring for 30 min at room temperature, Et₂O (100mL) was added and the mixture was washed successively with 10% citricacid (25 mL), 5% NaHCO₃ (25 mL) and brine (25 mL). After drying overMgSO₄, the solution was concentrated to give the diazomethylketone as ayellow foam (0.300 g).

The diazomethylketone from above (0.300 g, 0.5 mmol) was dissolved inEtOAc (3 mL) and cooled to −15° C. A solution of HBr in AcOH (48% w/w,100 μL) was added dropwise and the reaction mixture stirred for 5 min.The reaction was warmed to room temperature and volatiles removed undera stream of nitrogen. The residue was dissolved in MeCN (5 mL) andthiourea (0.075 g, 1.0 mmol) was added. After stirring for 45 min at 60°C., the reaction mixture was cooled and the solvent removed under astream on nitrogen. Water (0.5 mL) was added followed by 4 N HCl indioxane (5 mL) and the mixture stirred for 30 min. Dioxane wasevaporated under reduced pressure and 1 N HCl (10 mL) was added. Theaqueous phase was washed with ether (3×10 mL) and liophilized to give abrown foam. The material was coevaporated once with MeOH then with MeCNto give a pale yellow solid (0.150 g).

The hydrochloride salt from above was coupled to the carboxylic acid ofexample 2 in the usual manner to give, after purification by preparativeC18 reversed-phase HPLC, the title compound of example 111.

Example 112(S)-3-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-4-(5-hydroxy-1H-indol-3-yl)-butyricacid (Entry 16061, Table 16)

The diazomethylketone of example 111 (0.100 g, 0.17 mmol) was dissolvedin a mixture of THF (0.2 mL) and MeOH (0.3 mL). A solution of silverbenzoate in triethylamine (100 mg/mL, 0.1 mL) was added slowly, causingvigorous gas evolution. After 1 min, the reaction mixture turned brown.It was diluted with ether (2 mL) and 4N HCl in dioxane (0.2 mL) wasadded. The precipitate that formed was removed by filtration (ether forwashings) and the filtrate evaporated to dryness. It was then stirredwith additional 4N HCl in dioxane (0.5 mL) for 1 h. Et₂O (10 mL) and 1 NHCl (10 mL) were added and the aqueous phase was liophilized to give ayellow residue (0.078 g).

The amine hydrochloride from above was coupled to the carboxylic acid ofexample 2 in the usual manner, saponified and purified by preparativeC18 reversed-phase HPLC to give the title compound of example 112).

Example 113 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-carbamoyl-2-(5-hydroxy-1-methyl-1H-indol-3-yl)-ethyl]-amide(Entry 13002, Table 13)

5-Hydroxy-(S)-tryptophan methyl ester hydrochloride (6.47 g, 23.9 mmol)was suspended in DCM (150 mL) and the suspension cooled in an ice bath.DIEA (4.17 mL, 23.9 mmol) was added followed by di-tert-butyldicarbonate(5.22 g, 23.9 mmol) in DCM (5 mL). The mixture was stirred for 3 h atroom temperature after which additional DIEA (0.75 mL) anddi-tert-butyldicarbonate (0.50 g) was added. After stirring for anotherhour at room temperature, the solution was washed with 5% citric acid(4×50 mL) and brine (2×50 mL). The extract was dried (MgSO₄) andconcentrated to a dark beige solid. The crude material was trituratedwith 5% Et₂O in hexane (75 mL), filtered and dried to give the desiredcarbamate ester (7.81 g).

The carbamate from above (1.037 g, 3.1 mmol) was dissolved in DMF (10mL). Imidazole (0.422 g, 6.2 mmol) and tert-butyldiphenylsilyl chloride(0.847 mL, 3.26 mmol) were added and the mixture stirred overnight atroom temperature. Water (50 mL) was added and the mixture extracted withEt₂O (2×50 mL). The extract was washed with 10% citric acid (25 mL), 5%NaHCO₃ (25 mL) and brine (25 mL). The solution was dried (MgSO₄) andevaporated to give the fully protected 5-hydroxytryptophan derivative asa white foam (1.738 g).

The protected tryptophan derivative from above (0.573 g, 1.00 mmol) wasdissolved in DMF (3 mL) and the solution cooled in ice. Sodium hydride(60% oil dispersion, 0.048 g, 1.2 mmol) was added and the mixturestirred for 30 min. Iodomethane (0.093 mL, 1.5 mmol) was added andstirring continued for an additional hour. The reaction was thenquenched with 10% citric acid (2 mL) and water (25 mL), and extractedwith Et₂O (100 mL). The extract was dried (MgSO₄) and concentrated, andthe residue purified by flash chromatography (20-30% EtOAc/hexane aseluent) to give the desired N-methyltryptophan derivative (0.284g).

The N-methyltryptophan derivative from above (0.711 g, 1.21 mmol) wasdissolved in MeOH (10 mL) and thionyl chloride (0.6 mL) was addeddropwise. The mixture was heated to 60° C. for 3 h. Volatiles wereremoved under reduced pressure and the residue triturated with TBME (25mL). The precipitated white solid was collected, washed with TBME anddried to give N-methyl-5-hydroxytryptophan methyl ester hydrochloride(0.339 g): MS (ES⁺) m/z 249 (MH⁺).

The methyl ester hydrochloride from above (0.170 g, 0.6 mmol) wassuspended in concentrated aqueous ammonia (15 mL) and the mixture wasstirred overnight at room temperature. Volatiles were then removed undervacuum and the residue triturated with MeOH (3-4 mL) and Et₂O (15 mL).The amide derivative was obtained as a brown solid (0.136 g).

The tryptophan amide derivative from above was coupled to the carboxylicacid of example 2 in the usual manner to give after purification by HPLCthe title compound of example 113.

Example 114(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-hydroxy-1-methyl-1H-indol-3-yl)-propionicacid methyl ester (Entry 11028, Table 11)

N-Methyl-5-hydroxytryptophan methyl ester hydrochloride (example 113)was coupled to the carboxylic acid of example 2 in the usual manner togive after purification by HPLC the title compound of example 114.

Example 115(S)-3-[5-(1-Carboxy-1-methyl-ethoxy)-1-methyl-1H-indol-3-yl]-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid methyl ester (Entry 11029, Table 11)

The title compound of example 114 (0.097 g, 0.18 mmol) was dissolved inacetone (1.5 mL). Cesium carbonate (0.175 g, 0.54 mmol) andtert-butylbromoisobutyrate (0.080 g, 0.36 mmol) were added and themixture stirred at 60° C. overnight in a sealed tube. The reactionmixture was then diluted with water (10 mL) and the product extractedwith EtOAc (50 mL). The organic phase was dried (MgSO₄), concentratedand the residue purified by flash chromatography using 60-80% EtOAc inhexane as eluent. The purified diester was dissolved in DCM (0.5 mL) andTFA (0.5 mL) was added. After stirring at room temperature for 1.5 h,volatiles were removed under a stream of nitrogen and the residuepurified by preparative C18 reversed-phase HPLC to give the titlecompound of example 115.

Example 116(S)-3-[5-(1-Carboxy-1-methyl-ethoxy)-1-methyl-1H-indol-3-yl]-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 11030, Table 11)

The title compound of example 115 (6 mg) was dissolved in DMSO (0.4 mL)and 2.5N NaOH (0.2 mL) was added. After stirring for 30 min at roomtemperature, the reaction mixture was acidified with TFA (0.1 mL) andthe product of example 116 isolated directly by preparative C18reversed-phase HPLC.

Example 1172-[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1-methyl-1H-indol-5-yloxy]-2-methyl-propionicacid (Entry 1176, Table 1)

Following the procedure described for example 115, the title compound ofexample 113 was alkylated with tert-butylbromoisobutyrate and theprotecting group removed to give the title compound of example 117 afterpurification by preparative C18 reversed-phase HPLC.

Example 118[3-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-1-methyl-1H-indol-5-yloxy]-aceticacid (Entry 13003, Table 13)

Following the procedure described for example 117, the title compound ofexample 113 was alkylated with tert-butylbromoacetate and the protectinggroup removed to give the title compound of example 118 afterpurification by preparative C18 reversed-phase HPLC.

Example 119 Substituted Racemic Phenylalanine Fragments

A variety of racemic substituted phenylalanine derivatives were preparedfrom the corresponding bromobenzene derivatives via palladium-catalyzedHeck coupling with 2-acetamido methyl acrylate as described in thescheme below. For this purpose, phenolic functions were protected asacetate and carboxyl groups as methyl esters. Following Heck coupling,the resulting protected dehydroamino acids were hydrogenated to theracemic phenylalanine derivatives which were deprotected to the freeamino acids by hydrolysis under acidic conditions. Free carboxylic acidfunctions were then reprotected as methyl esters prior to coupling withthe carboxylic acid of example 2. The following examples arerepresentative and are meant to illustrate the process:

Racemic 3-fluoro4-(carboxymethyl)phenylalanine methyl esterhydrochloride

4-Bromo-2-fluorobenzoic acid (3.00 g, 13.7 mmol) was dissolved in MeOH(25 mL) and thionyl chloride (1.5 mL, 20.1 mmol) was added dropwise. Themixture was refluxed overnight and then volatiles were removed underreduced pressure. The residue was triturated with a small amount of MeOHand the methyl ester collected by filtration (3.02 g).

The methyl ester from above (2.66 g, 11.4 mmol) was dissolved in MeCN(15 mL) and triethylamine (4.0 mL, 28.5 mmol) was added, followed by2-acetamido methyl acrylate (1.80 g, 12.6 mmol) and tri-o-tolylphosphine(0.28 g, 0.91 mmol). The mixture was degassed with argon for 15 min andpalladium acetate (0.17 g, 0.80 mmol) was added. Following an additional15 min of degassing, the mixture was refluxed for 20 h. EtOAc was addedand the solution washed with water, dried (MgSO₄) and concentrated. Theresidue was crystallized from EtOAc to give the desired dehydroaminoester (1.30 g).

The dehydroaminoester from above was dissolved in MeOH and hydrogenatedover 20% Pd(OH)₂ under one atmosphere of hydrogen gas for 20 h. Afterremoval of the catalyst by filtration and removal of the solvent underreduced pressure, the desired protected phenylalanine derivative wasobtained.

The protected phenylalanine derivative from above (0.210 g, 0.71 mmol)was added to 4N HCl and the mixture refluxed overnight. Volatiles werethen removed under vacuum to give the desired free amino acid as thehydrochloride salt (0.182 g). The fully deprotected phenylalaninederivative from above (0.187 g, 0.69 mmol) was dissolved in MeOH (30 mL)and thionyl chloride (3 mL) was added dropwise. The mixture was refluxedovernight and then evaporated under vacuum. The residue was trituratedwith MeOH to give the title compound (0.193 g).

Following adaptations of the above protocols, the following racemicphenylalanine esters were prepared:

Example 120 Racemic4-(2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-fluoro-benzoicacid (Entry 1142, Table 1)

Racemic 3-fluoro-4-(carbomethoxy)phenylalanine methyl esterhydrochloride (example 119) was coupled to the carboxylic acid ofexample 2 in the usual manner and saponified to give the title compoundof example 120.

Example 121 Racemic5-(2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-hydroxy-benzoicacid (Entry 16058, Table 16)

Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usual mannerand saponified to give the title compound of example 121.

Example 122 Racemic3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 1152, Table 1)

Racemic 3-chloro-5-methyltyrosine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usual mannerand saponified to give the title compound of example 121.

Example 123 Racemic2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(3,5-difluoro-4-hydroxy-phenyl)-propionicacid (Entry 1153, Table 1)

Racemic 3,5-difluorotyrosine methyl ester hydrochloride (example 119)was coupled to the carboxylic acid of example 2 in the usual manner andsaponified to give the title compound of example 123.

Example 124 Racemic3-(2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-benzoicacid (Entry 16053, Table 16)

Racemic 3-(carbomethoxy)phenylalanine methyl ester hydrochloride(example 119) was coupled to the carboxylic acid of example 2 in theusual manner and saponified to give the title compound of example 1234.

Example 125 Racemic3-(4-Carboxymethoxy-3,5-difluoro-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 1144, Table 1)

Racemic 3,5-difluorotyrosine methyl ester hydrochloride (example 119)was coupled to the carboxylic acid of example 2 in the usual manner. Thephenolic hydroxyl group was alkylated with methyl bromoacetate in theusual manner (K₂CO₃/acetone at reflux) and ester groups saponified togive the title compound of example 125.

Example 126 Racemic5-(2-Carboxy-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-carboxymethoxy-benzoicacid (Entry 16054, Table 16)

Racemic 3-(carbomethoxy)tyrosine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usualmanner. The phenolic hydroxyl group was alkylated with methylbromoacetate in the usual manner (K₂CO₃/acetone at reflux) andsaponified to give the title compound of example 126.

Example 127 Racemic3-(4-Carboxymethoxy-3-chloro-5-methyl-phenyl)-2-{[1-(1-cyclohexyl-2furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 16055, Table 16)

Racemic 3-chloro-5-methyltyrosine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usualmanner. The phenolic hydroxyl group was alkylated with methylbromoacetate in the usual manner (K₂CO₃/acetone at reflux) and estergroups saponified to give the title compound of example 127.

Example 128 Racemic2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(6-hydroxy-naphthalen-2-yl)-propionicacid (Entry 21001, Table 21)

Racemic 5-hydroxynaphthylalanine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usual mannerand saponified to give the title compound of example 128.

Example 129 Racemic3-(6-Carboxymethoxy-naphthalen-2-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 21002, Table 21)

Racemic 5-hydroxynaphthylalanine methyl ester hydrochloride (example119) was coupled to the carboxylic acid of example 2 in the usualmanner. The phenolic hydroxyl group was alkylated with methylbromoacetate in the usual manner (K₂CO₃/acetone at reflux) and estergroups saponified to give the title compound of example 129.

Example 130 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-amino-thiazol-4-yl)-2-(5-hydroxy-1-methyl-1H-indol-3-yl)-ethyl]-amide(Entry 14003, Table 14)

N,O-Bis-Boc-5-hydroxy-L-tryptophan (Example 86, 0.600 g, 1.43 mmol) wasconverted to its methyl ester using diazomethane in Et₂O. Followingremoval of volatiles under reduced pressure, the residue was dissolvedin DMF and the solution cooled in ice. Iodomethane (0.178 mL, 2.86 mmol)was added followed by a 60% oil dispersion of NaH (0.086 g, 2.14 mmol).The mixture was stirred in the ice bath for 1 h and then quenched withAcOH (0.20 mL). Water (15 mL) was added and the mixture extracted withEt₂O (2×50 mL). The extract was dried (MgSO₄) and concentrated and theresidue purified by flash chromatography (25%-50% EtOAc in hexane aseluent) to give the N-methyltryptophan derivative as a white foam (0.400g).

The methyl ester from above (0.385 g, 0.86 mmol) was dissolved in THF (4mL). Water (0.8 mL) and lithium hydroxide monohydrate (0.036 g, 0.86mmol) was added and the mixture stirred vigorously for 1 h at roomtemperature. The mixture was poured into a solution of K₂CO₃ (1.0 9) inwater (30 mL) and the solution washed with ether (2×25 mL). The aqueousphase was acidified to pH 4 by slow addition of 4 N HCl and extractedwith Et₂O ( 2×25 mL). The extract was dried (Na₂SO₄) and evaporated togive the free carboxylic acid as a white foam (0.346 g).

The free acid from above (0.334 g, 0.77 mmol) was dissolved in THF (5mL) and the solution cooled to −20 C. DIEA (0.200 mL, 1.15 mmol) andisobutylchloroformate (0.130 mL, 1.0 mmol) were added and the mixturestirred for 2 h at −20 C. Additional DIEA (0.100 mL) andisobutylchloroformate (0.065 mL) were added to complete the reaction(additional 30 min). Diazomethane (0.6 M in Et₂O, 10 ml) was added andstirring continued for another hour. Et₂O (100 mL) was added and thesolution washed successively with 10% citric acid (2×20 mL) andsaturated aqueous NaHCO₃ (20 mL). The extract was dried (MgSO₄) andconcentrated to give a residue that was purified by flash chromatographyusing 40-50% EtOAc in hexane as eluent. The diazomethylketone derivative(0.294 g) was obtained as a yellow foam.

The diazomethylketone was converted to the bromomethylketone with 48%HBr in AcOH as described previously (Example 86).

The bromomethylketone from above was converted to the aminothiazolederivative with thiourea as described previously (Example 91).

The thiazole derivative obtained above was deprotected using 50% TFA inDCM and the hydrochloride derivative was coupled to the carboxylic acidof example 2 to give the title compound of example 130.

Example 131(S)-3-[5-(2-{[2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino}-ethanoylamino)-1H-indol-3-yl]-2-{[1-(cyclohexyl-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 111031, Table 11)

The 5-aminotryptophan methyl ester derivative of example 48 was coupledto ethylenediamine tetraAcetic acid trimethylester in the usual mannerand the product saponified to give the title compound of example 131.

Example 132 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13014, Table 13)

N-Boc-5-hydroxytryptophan methyl ester (example 113, 0.500 g, 1.5 mmol)was dissolved in MeOH (4 mL) and 2 N NaOH (2.24 mL, 4.5 mmol) was added.The mixture was stirred under an atmosphere of argon for 3 h. Thesolution was then added to a vigorously stirred 1 N KHSO₄ (15 mL). After10 min the solid was filtered and air dried 18 h.

To the carboxylic acid prepared above (0.157 g, 0.5 mmol) in DMF (2 mL)were added TBTU (0.157 g, 0.5 mmol) and DIEA (256 μL, 1.5 mmol). Thesolution was stirred 30 min at room temperature and serinol (0.045 g,0.5 mmol) was added. After 2 h the solution was poured into 50% NaCl(100 mL) and the product extracted with EtOAC (25 mL). The organicsolution was washed with 5% citric acid (2×50 mL), 5% NaHCO₃ (3×50 mL)and brine (50 mL). The extract was dried (MgSO₄) and evaporated to yield105 mg of the 5-hydroxytryptophan amide. The Boc derivative preparedabove was deprotected with 4N HCl-dioxane and coupled with the acid ofexample 2 in the usual manner to give the title compound of example 132.

Example 133 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-dimethylamino-ethylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13015, Table 15)

The carboxylic acid from example 2 was coupled to(S)-5-hydroxytryptophan methyl ester hydrochloride and the methyl estersaponified in the usual manner.

The carboxylic acid from above was coupled with N,N-dimethylethylenediamine under standard TBTU conditions example to yield the titlecompound of example 133.

Example 134 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-hydroxy-ethylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13016, Table 13)

The carboxylic acid from example 133 was coupled to aminoethanol understandard TBTU conditions to yield the title compound of example 134.

Example 135 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide(Entry13017, Table 13)

The carboxylic acid of example 133 was coupled to aminoethylmorpholineunder standard TBTU conditions to yield the title compound of example135.

Example 136 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(3-dimethylamino-propylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13018, Table 13)

The carboxylic acid of example 133 was coupled todimethylaminopropylamine under standard TBTU conditions to yield thetitle compound of example 136.

Example 137 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-2-(5-hydroxy-1H-indol-3-yl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide(Entry 13019, Table 13)

The carboxylic acid of example 133 was coupled to1-(2-aminoethyl)pyrrolidine under standard TBTU conditions to yield thetitle compound of example 137.

Example 138 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid{(S)-2-(5-hydroxy-1H-indol-3-yl)-1-[2(RS)-(1-methyl-pyrrolidin-2-yl)-ethylcarbamoyl]-ethyl}-amide(Entry 13020, Table 13)

The carboxylic acid of example 133 was coupled to2-(2-aminoethyl-1-methyl) pyrrolidine under standard TBTU conditions toyield the title compound of example 138.

Example 139 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry 13021, Table 13)

The carboxylic acid of example 133 was coupled to2amino-2-methyl-1-propanol under standard TBTU conditions to yield thetitle compound of example 139.

Example 140 1-Cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid[(S)-1-(2(RS),3-dihydroxy-propylcarbamoyl)-2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide(Entry13022, Table 13)

The carboxylic acid of example 133 was coupled to racemic3-amino-1,2-propanediol under standard TBTU conditions to yield thetitle compound of example 140.

Example 141(S)-3-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-4-(4-hydroxy-phenyl)-butyricacid (Entry 1230, Table 1)

The diazomethylketone derived from Bis-Boc-Tyr (Example 64, 0.750 g,1.85 mmol) was dissolved in a 1/1 mixture of THF/MeOH (10 mL). Asolution of silver benzoate (50 mg) in triethylamine (1 mL) was added.After 15 min of stirring at room temperature the solvent was evaporatedand the residue purified by flash chromatography (gradient 10-25%EtOAc/hexane) to yield 749 mg of protected β-tyrosine methyl ester.

The bis-Boc derivative prepared above was deprotected with 4N HCl indioxane and coupled with the acid of example 2 in the usual manner.Following saponification of the methyl ester, the title compound ofexample 141 was obtained.

Example 142(E)-3-[5-((S)-2-Carbamoyl-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-ethyl)-2-hydroxy-phenyl]-acrylicacid (Entry 16062, Table 16)

To a solution of N-Boc-3-iodotyrosine (0.380 g, 0.93 mmol) in pyridine(1 mL) were added acetic anhydride (105 μL, 1.1 mmol) and DMAP (10 mg,cat). The solution was stirred 1.5 h then diluted in 5% citric acid (20mL), and the product extracted with EtOAc. The organic solution wasevaporated and the residue dissolved in MeCN (4 mL). To the stirred cold(ice bath) solution were added EDC (0.196 g, 1.0 mmol) and HOBt (0.135g, 1.0 mmol). After stirring for 1 h, a 2 N solution of ammonia in iPrOH(3 mL) was added. The suspension was stirred 1 h at 5° C., the solid wasfiltered, the filtrate evaporated and the residue purified by flashchromatography (gradient 3-5% MeOH/chloroform) to yieldN-Boc-O-acety-3-iodotyrosine amide.

The iodo tyrosine derivative prepared above was coupled to methylacrylate according to the procedure of example 83: MS (ES⁺) m/z 307(MH⁺-Boc). The N-Boc-tyrosine derivative prepared above was deprotectedwith 4 N HCl in dioxane and coupled with the acid of example 2 in theusual manner. Following saponification of the O-acetyl group the titlecompound of example 142 was obtained.

Example 1434-{N′-[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-hydrazinocarbonyl}-benzoicacid (Entry 1302, Table 1)

The benzimidazole carboxylic acid of example 2 (0.500 g, 1.61 mmol) wasstirred in DMF (10 mL) with N-Cbz-hydrazine (0.268 g, 1.61 mmol), TBTU(0.620 g, 1.93 mmol) and DIEA (0.727 g, 563 mmol) for 3 days. EtOAc wasadded and the reaction mixture was washed twice with 10% aqueous citricacid, twice with saturated aqueous NaHCO₃ and once with brine. Theorganic layer was dried over anhydrous MgSO₄, filtered and concentratedto give a brown foam that was hydrogenolyzed in THF-EtOH (1:1) with 10%Pd/C (70 mg) under an atmosphere of hydrogen for 8 h. The suspension wasfiltered and concentrated to dryness to give1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid hydrazideas a brown foam.

1-Cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid hydrazide(0.022 g, 0.068 mmol) and methyl-4-chlorocarbonylbenzoate (0.013 g,0.068 mmol) were stirred in DMF (1 mL) in the presence of DIEA (0.018 g,0.14 mmol) for 2 h. An aqueous solution of NaOH (2.5 N, 0.22 mL, 0.55mmol) was then added and the mixture was stirred for 2 h at roomtemperature. The reaction mixture was acidified by the addition of AcOHand purified by reversed phase C18 preparative HPLC to give the titlecompound of example 143.

Example 144 Racemic1-cyclohexyl-2-furan-3-yl-1H-benzimidazole-5-carboxylic acid1-carboxy-2-(4-carboxymethoxy-phenyl)-ethyl ester (Entry 5005, Table 5)

Racemic 2-hydroxy-3-(4-hydroxyphenyl)-propionic acid (0.100 g, 0.55mmol) was stirred in acetone (10 mL) with triethylamine (0.17 mL, 1.2mmol) and benzyl bromide (0.14 mL, 2.2 mmol) for 16 h at roomtemperature. The mixture was concentrated to dryness, taken up in EtOAcand washed once with water and twice with brine, dried over anhydrousMgSO₄, filtered and concentrated to dryness. The crude product waspurified by flash chromatography to give the benzyl ester (150 mg). Theester (150 mg) was then dissolved in acetone (10 mL), t-butylbromoacetate (0.1 mL, 0.65 mmol) and cesium carbonate (0.540 g, 1.7mmol) were added and the reaction was stirred at 50° C. for 2.5 h. Themixture was concentrated to dryness, taken up in EtOAc and washed oncewith water and twice with brine, dried over anhydrous MgSO₄, filteredand concentrated to dryness. The crude product was purified by flashcolumn chromatography, using 20% EtOAc in hexane as eluent, to give3-(4-t-butoxycarbonylmethoxyphenyl)-2-hydroxy-propionic acid benzylester in 70% yield (146 mg).

To a solution of the above compound (0.060 g, 0.155 mmol) in DCM (5 mL),the carboxylic acid of example 2 (0.058 g, 0.19 mmol), DCC (0.039 g,0.19 mmol) and DMAP (0.023 g, 0.19 mmol) were added and the reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas then concentrated and purified by flash chromatography to give 160mg of 1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carboxylic acid1-benzyloxycarbonyl-2-(4-tert-butoxycarbonylmethoxy-phenyl)-ethyl ester.

The benzyl ester from above (0.040 g, 0.059 mmol) was stirred in amixture of EtOAc:EtOH (4 mL, 3:1 ratio) with 10% Pd/C (10 mg) under anatmosphere of hydrogen gas for 4 h. The suspension was filtered andconcentrated, then dissolved in 1 mL of 4 N HCl in dioxane and stirredfor 1 h. The mixture was concentrated to dryness and purified byreversed phase C18 preparative HPLC to give the title compound ofexample 143.

Example 145 Racemic2-(3-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propanoylamino)-3-(3H-imidazol-4-yl)-propionicacid (Entry 1228, Table 1)

The carboxylic acid of example 2 (0.550 g, 1.8 mmol) was dissolved inSOCl₂(20 mL) and DMF (˜0.1 mL). The reaction mixture was stirred at roomtemperature for 20 h and then concentrated to dryness and co-evaporatewith EtOAc to give a1-cyclohexyl-2-furan-3-yl-1H-benzoimidazole-5-carbonyl chloride as abrown solid (580 mg). The acid chloride (0.050 g, 0.16 mmol) wasdissolved in DMF (1 mL) and reacted with I-carnosine (0.036 g, 0.159mmol) in the presence of DIEA (82 μL, 0.476 mmol). The reaction mixturewas stirred for 3 days at room temperature before it was acidified withAcOH (1 mL) and purified by reversed phase C18 preparative HPLC. Thetitle compound of example 145 was obtained as a white solid.

Example 146(S)-3-(3-Azido-4-hydroxy-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 1248, Table 1)

To a solution of 3-amino-L-tyrosine.2HCl.H₂O (2.50 g, 8.8 mmol) in 0.5 NHCl (28 mL) at 0° C., an aqueous solution of NaNO₂ (0.724 g, 10.5 mmol,in 10 mL H₂O) was added slowly. The reaction mixture was stirred for 10min at 0° C., in the dark, and then a solution of NaN₃ (1.43 g, 21.9mmol, in 10 mL H₂O) was added and stirring was continued for 1 h at 0°C. The white solid formed was filtered and dried to give(S)-2-amino-3-(3-azido-4-hydroxy-phenyl)-propionic acid (1.16 g) as of abeige solid. This amino acid was coupled to the carboxylic acid ofexample 2 in the usual manner to give the title compound of example 146after purification by preparative C18 reversed-phase HPLC.

Example 147(S)-3-(3-Azido-4-carboxymethoxy-phenyl)-2-{[-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 16063, Table 16)

(S)-3-(3-Azido-4-hydroxy-phenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionicacid (Example 146, 0.230 g, 0.44 mmol) and methyl bromoacetate (0.136 g,0.89 mmol) were stirred in acetone (4 mL) in the presence of Cs₂CO₃(0.058 g, 0.18 mmol) for 20 h at room temperature. The reaction mixturewas concentrated to dryness and dissolved in water, acidify to pH 4 andextracted with EtOAc (3×). The combined organic layers were dried overanhydrous MgSO₄ and concentrated to give a brown oil. This oil wasstirred in THF:MeOH (6 mL, 2:1 ratio) in the presence of LiOHmonohydrate (0.18 mmol) for 3 h at room temperature. The reactionmixture was concentrated to remove most of the THF and MeOH, acidifiedwith AcOH and purified by reversed phase C18 preparative HPLC to obtainthe title compound of example 147.

Example 1481-Cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridine-5-carboxylic acid(Entry 5001, Table 5)

3-Methoxy-6-methyl-2-nitro-pyridine

A solution of 3-hydroxy-6-methyl-2-nitropyridine (4.00 g, 26 mmol) inMeOH-DCM (30 mL, 2:1 ratio) was treated with diazomethane in Et₂O untilall starting material was converted to3-methoxy-6-methyl-2-nitropyridine (TLC). The solution was concentratedto dryness to give the desired product as a yellow solid (4.25 g).

5-Methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester

A solution of 3-methoxy-6-methyl-2-nitro-pyridine (2.25 g, 13.4 mmol) inH₂O containing MgSO₄ (5.24 g, 43.7 mmol) was heated to reflux. Asolution of KMnO₄ (5.72 g, 36.2 mmol) was added slowly over a period of1 h and reflux was maintained for an additional 5 h. The reactionmixture was cooled to room temperature and concentrated ammonia wasadded (6 mL). The brown solid formed was filtered and washed twice withwater. The filtrate was concentrated and the new precipitate formed,composed mostly of starting material, was removed by filtration. Thefiltrate was acidified and extracted twice with EtOAc. The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄,filtered and concentrated. The residue was taken up in MeOH-DCM (40 mL,1:1 ratio) and a solution of diazomethane in Et₂O was added until apersisting yellow color was observed. The solution was then concentratedto dryness and purify by flash column chromatography, using a gradientof hexane/EtOAc from 6/4 to 4/6 as the eluent, to give5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester (585 mg).

5-Cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester

A solution of 5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester(0.585 g, 2.75 mmol) and cyclohexylamine (0.636 mL, 5.51 mmol) in DMF(8mL) was heated at 70° C. for 20 h. The mixture was poured on brine (50mL) while mixing vigorously. The solid formed was filtered, washed withwater and then dissolved in EtOAc. The solution was washed with water,saturated NaHCO₃ and brine, dried over anhydrous MgSO₄, filtered andconcentrated to give 5-cyclohexylamino-6-nitro-pyridine-2-carboxylicacid methyl ester as a brown oil (0.558 g) which was used in thesubsequent step without purification.

6-Amino-5-cyclohexylamino-pyridine-2-carboxylic acid methyl ester

The crude 5-cyclohexyl-6-nitro-pyridine-2-carboxylic acid methyl esterfrom above 0.530 g, 1.90 mmol) was stirred in EtOH (10 mL) and 10% Pd/C(50 mg), under 1 atm of H₂ gas at room temperature for 3 days. Thesuspension was filtered through a pad of celite and concentrated todryness. The product was purified by flash column chromatography, usinga gradient from 60% hexane in EtOAc to 100% EtOAc as the eluent, to give6-amino-5-cyclohexylamino-pyridine-2-carboxylic acid methyl ester (0.210g).

1-Cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridine-5-carboxylic acidmethyl ester

To a solution of the methyl ester from above (0.100 g, 0.40 mmol) in DMF(3 mL) and H₂O (0.300 mL), oxone® (0.813 g, 1.32 mmol) and 3-furaldehyde(0.138 g, 1.32 mmol) were added. The reaction mixture was stirred atroom temperature for 5 h and then stored at 5° C. for 3 days. Themixture was diluted with EtOAc and washed twice with water, twice withsaturated NaHCO₃ and once with brine. The organic layer was then driedover magnesium sulfate, filtered and concentrated to give an oil thatwas purified by flash chromatography, using EtOAc as the eluent, to give1-cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridine-5-carboxylic acidmethyl ester (0.058 g).

1-Cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridine-5-carboxylic acid(Entry 5001, Table 5)

The ester from above (0.058 g, 0.178 mmol) was dissolved in MeOH (2 mL)and aqueous LiOH (0.700 mL, 1 M) was added. The solution was stirred atroom temperature for 2 h and then purified by C18 reversed phasepreparative HPLC to give the title compound of example 148.

Example 149(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridin-5-yl)-methanoyl]-amino}-3-(5-hydroxy-1H-indol-3-yl)-propionicacid (Entry 5002, Table 5)

The carboxylic acid derivative of example 148 was coupled to5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner.Saponification followed by purification by preparative C18reversed-phase HPLC gave the title compound of example 149.

Example 150(S)-3-(5-Carboxymethoxy-1-carboxymethyl-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-imidazo[4,5-b]pyridin-5-yl)-methanoyl]-amino}-propionicacid (Entry 5003, Table 5)

The carboxylic acid derivative of example 148 was coupled to5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner.The material was then alkylated with excess methyl bromoacetate asdescribed previously to give after deprotection by saponification andpreparative C18 reversed-phase HPLC, the title compound of example 150.

Example 1511-Cyclohexyl-2-furan-3-yl-4-methyl-1H-benzimidazole-5-carboxylic acid(Entry 5004, Table 5)

4-Chloro-2-methylbenzoic

In a dry round-bottomed flask (3 L) equipped with a mechanical stirrerunder N₂, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA,99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added andthe mixture was cooled to −90° C. in a bath of liquid N₂/EtOH. Freshlytitrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) wasadded slowly via cannula as to maintain the temperature at −50° C. Thesolution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirringcarefully to maintain the temperature at −90° C. The reaction mixturewas stirred at −90° C. for 1 h before allowed to warm-up to −80° C. andCH₃I (80 mL, 1.28 moles) was added very slowly. The reaction mixture wasstirred for 10 min at −80° C., then quenched slowly with H₂O (600 mL)and allowed to warm-up to room temperature. The aqueous layer wasseparated, washed with Et₂O (2×500 mL) and then acidified with HCl (2.5N, 600 mL) while cooling in an ice bath; cooling was continued for 16 hat 4° C. to allow crystallization of the desired product. The crudeproduct was dried under vacuum and over anhydrous P₂O₅ and thenre-crystallized from hot toluene (700 mL) to obtain pure4-chloro-2-methylbenzoic acid (40 g).

Mixture of 4-chloro-2-methyl-5-nitrobenzoic acid methyl ester and4-chloro-2-methyl-3-nitrobenzoic acid methyl ester

These compounds were prepared using a modification of the procedurereported by M. Baumgarth et al. (J. Med. Chem. 1997, 40, 2017-2034).4-Chloro-2-methylbenzoic acid (6 g) was added to fuming HNO₃ (100%, 36g) in small portions over a period of 20 min, at 10° C., while stirringvigorously. The reaction mixture was stirred vigorously for a period of1 h and the temperature allowed to warm-up to 20° C. The reactionmixture was then poured onto ice (100 g) and the yellow precipitateformed was collected, washed with H₂O, dissolved in EtOAc (25 mL) andthe solution was dried over Na₂CO₃ and filtered. After concentration ofthe remaining mother liquor to ½ of the original volume, moreprecipitate was formed, however, the solid formed was always a mixtureof 4-chloro-2-methyl-5-nitrobenzoic acid and4-chloro-2-methyl-3-nitrobenzoic acid. Thus, all of the solid materialformed was collected by filtration (6.5 g), stirred in MeOH/HCl at 0° C.for 1 h to form a mixture of methyl esters. This mixture was used in thefollowing step without further purification.

4-Cyclohexylamino-2-methyl-5-nitrobenzoic acid methyl ester and4-cyclohexylamino-2-methyl-3-nitrobenzoic acid methyl ester

The mixture of esters from above (1.1 g, 4.8 mmol) and cyclohexylamine(1.7 mL, 14.4 mmol) in DMSO (2 mL) were stirred at 60° C. for 16 h. Thereaction mixture was then cooled and poured onto ice (5 g) and mixedvigorously to allow the formation of a precipitate. The solid materialwas filtered, washed with H₂O and dissolved in EtOAc. The solution waswashed with H₂O and brine, dried over anhydrous MgSO₄ and evaporated toan oil containing the desired products. The oil was triturated withhexane (˜5 mL) to allow precipitation of relatively pure4-cyclohexylamino-2-methyl-5-nitrobenzoic acid methyl ester (600 mg),whereas the mother liquor contained mostly4-cyclohexylamino-2-methyl-3-nitrobenzoic acid methyl ester (600 mg).

3-Amino-4-cyclohexylamino-2-methylbenzoic acid methyl ester

4-Cyclohexylamino-2-methyl-3-nitrobenzoic acid methyl ester (150 mg) wasdissolved in THF/MeOH (30 mL, 1:2 ratio) and stirred in the presence ofH₂ (1 atm) and a catalytic amount of Pd(OH)₂ (20 mg) at room temperaturefor 14 h. The reaction mixture was then filtered, evaporated to drynessand purified by flash column chromatography, using 25% EtOAc in hexanewith 0.2% NH₄OH as the eluent, to give the pure aniline (106 mg).

1-Cyclohexyl-2-furan-3-yl-4-methyl-1H-benzimidazole-5-carboxylic acid

To a solution of the diamine from above (500 mg, 1.9 mmol) in DMF (3 mL)and H₂O (0.15 mL), 3-furaldehyde (0.22 mL, 2.5 mmol) and oxone® (1.29 g,2.1 mmol) were added and the reaction mixture was stirred at roomtemperature for 1 h. Subsequently, H₂O (60 mL) was added and the pH wasadjusted to 8 with aqueous NaHCO₃. The reaction mixture was thenextracted with DCM, the organic layer was washed with brine, dried overanhydrous Na₂SO₄ and evaporated to dryness. The desired benzimidazolemethyl ester (446 mg) was obtained pure after column chromatography,using 25% EtOAc in hexane.

Hydrolysis of the methyl ester was achieved with an aqueous solution ofNaOH (1.0 N, 0.66 mL, 6.6 mmol) in a solution of MeOH/THF (10 mL, 1:1ratio) at 60° C. for 1.5 h. The reaction mixture was then cooled to roomtemperature, the pH was adjusted to 4 with AcOH and the organic solventswere evaporated to dryness. The remaining aqueous mixture was extractedwith DCM (3×15 mL) and the combined organic layers were washed with H₂O,dried over anhydrous Na₂SO₄ and evaporated to dryness to give thedesired title compound of example 151,1-cyclohexyl-2-furan-3-yl4-methyl-1H-benzimidazole-5-carboxylic acid(392 mg).

Example 152(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-4-methyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-hydroxy-1H-indol-3-yl)-propionicacid (Entry 5007, Table 5)

The carboxylic acid derivative of example 151 was coupled to5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner.Saponification followed by purification by preparative C18reversed-phase HPLC gave the title compound of example 152.

Example 153(S)-3-(5-Carboxymethoxy-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-4-methyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-propionicacid (Entry 5008, Table 5)

The carboxylic acid derivative of example 152 was coupled to5-hydroxy-(S)-tryptophan methyl ester hydrochloride in the usual manner.The material was then alkylated with methyl bromoacetate as describedpreviously to give after deprotection by saponification and preparativeC18 reversed-phase HPLC, the title compound of example 153.

Example 154(S)-2-{[1-(1-Cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(5-hydroxy-1H-indol-3-yl)-propionicacid (Entry 5006, Table 5)

1-Cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazole-5-carboxylic acidwas prepared from 4-cyclohexylamino-2-methyl-5-nitrobenzoic acid methylester (Example 151) as described for the 4-methyl derivative (Example151). The acid was coupled to 5-hydroxy-(S)-tryptophan methyl esterhydrochloride in the usual manner and following saponification of themethyl ester and purification by preparative C18 reversed-phase HPLC,the title compound of example 154 was obtained.

Example 155(S)-3-(5-Carboxymethoxy-1H-indol-3-yl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazol-5-yl)-methanoyl]-amino}-propionicacid (Entry 5009, Table 5)

1-Cyclohexyl-2-furan-3-yl-6-methyl-1H-benzimidazole-5-carboxylic acidwas coupled to 5-hydroxy-(S)-tryptophan methyl ester hydrochloride inthe usual manner (Example 154). The material was then alkylated withmethyl bromoacetate as described previously to give after deprotectionby saponification and preparative C18 reversed-phase HPLC, the titlecompound of example 155. Example 156(E)-3-(4-{((S)-1-[1-(1-Cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-pyrrolidin-3-yloxy}-phenyl)-acrylicacid (Entry 6004, Table 6)

To a solution of (R)-(−)-3-pyrrolidinol hydrochloride (1.12 g, 9.1 mmol)in anhydrous THF (20 mL), a solution of di-tert-butyldicarbonate (2.07g, 9.5 mmol) in THF (15 mL), followed by DIEA (4.74 mL, 27.2 mmol) wereadded The reaction mixture was stirred at room temperature for 18 h thenthe solvent was evaporated. The residue was dissolved in EtOAc and thesolution was washed with 10% aqueous HCl, saturated NaHCO₃ and brine.The organic layer was dried over anhydrous MgSO₄ and then evaporated todryness to give the (R)-3-hydroxypyrrolidine-1-carboxylic acidtert-butyl ester as a white solid (1.54 g).

To a solution of 4-hydroxycinnamic acid (0.407 g, 2.48 mmol) in EtOAc, asolution of diazomethane in Et₂O was added until the yellow colorpersisted. Excess diazomethane was quenched by the addition of AcOH andthe reaction mixture was evaporated to dryness. The residue wasdissolved in EtOAc and washed with 10% aqueous HCl, saturated NaHCO₃ andbrine. The organic layer was dried over anhydrous MgSO₄ and evaporatedto dryness. The residue was purified by flash column chromatography,using a gradient from 10%-20% EtOAc in hexane, to giveE-3-(4-hydroxyphenyl)acrylic acid methyl ester as a white solid (0.362g). To a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acidtert-butyl ester (0.215 g, 1.15 mmol) in THF at 0° C.,triphenylphosphine (0.316 g, 1.21 mmol), diisopropyl azodicarboxylate(236 μL, 1.21 mmol) and E-3-(4-hydroxy-phenyl)-acrylic acid methyl ester(0.215 g, 1.21 mmol) were added. The reaction mixture was stirred for 2h at 0° C., followed by 4 h at room temperature and then the solvent wasevaporated in vacuo. The residue was purified by flash columnchromatography, using 20%-30% EtOAc in hexane, to give crude(S)-3-[4-(E)-2-methoxycarbonylvinyl)phenoxy]pyrrolidine-1-carboxylicacid tert-butyl ester as a yellow solid.

The product from above was dissolved in 4 N HCl in dioxane (4 mL) andstirred 30 min at room temperature. The solvent was evaporated todryness and the solid residue was triturated with EtOAc (3×) to give theamine hydrochloride product as a white solid (0.260 g).

The amine hydrochloride from above was coupled to the carboxylic acid ofexample 2 in the usual manner. Following ester hydrolysis under basicconditions and purification using reversed phase C18 HPLC the titlecompound of example 155 was obtained.

Example 157(S)-2-{[1-(1-Cycohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-amino}-3-(4-methoxycarbonylmethoxy-phenyl)-propionicacid (Entry 1124, Table 1)

The N-Boc-O-alkylated-L-tyrosine benzyl ester intermediate described inexample 98 was deprotected on nitrogen using 4 N HCl in dioxane andcoupled to the carboxylic acid of example 2. Following hydrogenolysis ofthe benzyl ester with Pd(OH)₂ and H₂ (gas), the title compound ofexample 157 was purified by preparative C18 reversed-phase HPLC.

Example 158(2S,4R)-4-[4-((Z)-2-Carboxy-vinyl)-phenoxy]-1-[1-(1-cyclohexyl-2-furan-3-yl-1H-benzimidazol-5-yl)-methanoyl]-pyrrolidine-2-carboxylicacid (Entry 6003, Table 6)

To a solution of N-Boc-protected cis-3-hydroxy-L-proline methyl ester(0.202 g, 0.82 mmol) in THF at 0° C., triphenylphosphine (0.433 g),diisopropylazodicarboxylate (333 uL) and E-3-(4-hydroxy-phenyl)-acrylicacid methyl ester (0.294 g) were added. The reaction mixture was stirredfor 2 h at 0° C., followed by 4 h at room temperature and then thesolvent was evaporated to dryness. The residue was purified by flashcolumn chromatography, using 10%-50% EtOAc in hexane, to give the crudeO-alkylated proline derivative as a yellow solid.

The material from above was dissolved in a 4N HCl in dioxane (10 mL) andstirred 30 min at room temperature. The solvent was evaporated todryness and the solid residue coupled to the carboxylic acid of example2 in the usual manner. Following saponification of ester protectinggroups the title compound of example 158 was purified by reversed phaseC18 HPLC.

The compounds of formula (I) can be obtained in the form oftherapeutically acceptable salts. (see, for example Pharmaceuticalsalts, Birge, S.M. et al., J. Pharm. Sci. (1977), 66, 1-19, incorporatedherein by reference).

Example 159 Inhibition of NS5B RNA Dependent RNA Polymerase Activity

The compounds of the invention were tested for inhibitory activityagainst the hepatitis C virus RNA dependant polymerase (NS5B), accordingto the following assay:

The substrates are:

a 12 nucleotide RNA oligo-uridylate (or oligo-uridine-monophosphate)(oligo-U) primer modified with biotin at the free 5′C position;

a complementary poly-adenylate (or adenosine monophospahte) (polyA)template of heterogeneous length (1000-10000 nucleotides); and UTP-[5,6³H].

Polymerase activity is measured as the incorporation of UMP-[5,6 ³H]into the chain elongated from the oligo-U primer. The ³H-labelledreaction product is captured by SPA-beads coated with streptavidin andquantified on the TopCount.

All solutions were made from DEPC treated MilliQ water [2 ml of DEPC isadded to 1 l of MilliQ water; the mixture is shaken vigorously todissolve the DEPC, then autoclaved at 121° C. for 30 minutes].

Enzyme

The full length HCV NS5B (SEQ ID NO.1) was purified as an N-terminalhexa-histidine fusion protein from baculovirus infected insect cells.The enzyme can be stored at −20° C. in storage buffer (see below). Underthese conditions, it was found to maintain activity for at least 6months.

Substrates

The biotinylated oligo-U₁₂ primer, the Poly(A) template, and theUTP-[5,6 ³H] were dissolved in water. The solutions can be stored at−80° C.

Assay Buffer

20 mM Tris-HCl pH 7.5

5 mM MgCl₂

25 mM KCl

1 mM EDTA

1 mM DTT

NS5B Storage Buffer

0.1 μM NS5B

25 mM Tris-HCl pH 7.5

300 mM NaCl

5 mM DTT

1 mM EDTA

0.1% n-Dodecyl maltoside

30% glycerol

Test Compound Cocktail

Just prior to assay, test compounds of the invention were dissolved inassay buffer containing 15% DMSO.

Substrate Cocktail

Just prior to assay, the substrates were mixed in assay buffer to thefollowing concentrations:

Final Concentration in Concentration in Component substrate cocktailassay RNAsin ™ 0.5 U/μl 1.67 U/μl Biotin-oligo-U₁₂ 3 ng/μl 1 ng/μlprimer PolyA template 30 ng/μl 10 ng/μl UTP-[5,6-³H]35 0.025 μCi/μl0.0083 μCi/μl Ci/mmol 0.25 μM UTP 2.25 μM 0.75 μM

Enzyme Cocktail

Just prior to assay, the RNA polymerase (NS5B) cocktail was prepared inassay buffer to the following specifications: Component Concentration incocktail

Component Concentration in cocktail Tris-HCl at pH 7.5 20 mM MgCl₂  5 mMKCl 25 mM EDTA  1 mM DTT  1 mM n-Dodecyl maltoside 1% NS5B 30 nM

Protocol

The assay reaction was performed in a Microfluor™ white “U” bottom plate(Dynatech™ #7105), by successively adding:

20 μl of test compound cocktail;

20 μl of substrate cocktail; and

20 μl of enzyme cocktail

(final [NS5B] in assay=10 nM; final [n-dodecyl maltoside] inassay=0.33%; final DMSO in assay=5%).

The reaction was incubated at room temperature for 1.5 hours. STOPsolution (20 μl; 0.5 M EDTA, 150 ng/μl tRNA) was added, followed by 30μl streptavidin coated PVT beads (8 mg/ml in 20 mM Tris-HCl, pH 7.5, 25mM KCl, 0.025% NaN₃). The plate was then shaken for 30 minutes. Asolution of CsCl was added (70 μl, 5 M), to bring the CsCl concentrationto 1.95 M. The mixture was then allowed to stand for 1 hour. The beadswere then counted on a Hewlett Packard TopCount™ instrument using thefollowing protocol:

Data mode: counts per minute

Scintillator: liq/plast

Energy range: low

Efficiency mode: normal

Region: 0-50

Count delay: 5 Minutes

Count time: 1 minute

Expected results: 6000 cpm/well

200 cpm/well no enzyme control

Based on the results at ten different concentrations of test compound,standard concentration-% inhibition curves were plotted and analysed todetermine IC₅₀'s for the compounds of the invention. For some compoundsthe IC₅₀ was estimated from two points.

Example 160 Specificity for NS5B RNA Dependent RNA Polymerase Inhibition

The compounds of the invention were tested for inhibitory activityagainst polio virus RNA dependent RNA polymerase and calf thymus DNAdependent RNA polymerase 11 in the format that is described for the HCVpolymerase with the exception that poliovirus polymerase was used inplace of the HCV NS5B polymerase.

Table of Compounds

The compounds listed in Tables 1 to 22 were found to be active in theabove-described NS5B assay, with IC₅₀'s of less than 25 μM. None ofthese compounds were found to exhibit significant inhibition ofpoliovirus RNA dependent RNA polymerase or calf thymus DNA dependent RNApolymerase II at 25 μM concentration.

In Tables 1 to 22, the following ranges apply: A: −25-10 μM; B: 10-5 μM;C: 5-1 μM; and D: <1 μM

TABLE 1

Entry # IC₅₀ μM R³ m/z 1001 A

486(MH⁺) 1002 A

512(MH⁺) 1003 B

518(MH⁺) 1004 C

474(MH⁺) 1005 C

400(MH⁺) 1006 B

502(MH⁺) 1007 C

386(MH⁺) 1008 C

430(MH⁺) 1009 C

488(MH⁺) 1010 C

472(MH⁺) 1011 C

474(MH⁺) 1012 C

478(MH⁺) 1013 C

532(MH⁺) 1014 C

474(MH⁺) 1030 B

530(MH⁺) 1015 B

458(MH⁺) 1016 C

545(MH⁺) 1017 B

503(MH⁺) 1019 C

519(MH⁺) 1020 C

476(MH⁺) 1021 C

460(MH⁺) 1022 C

488(MH⁺) 1023 C

474(MH⁺) 1024 C

483(MH⁺) D

497(MH⁺) 1025 B

430(MH⁺) 1026 C

474(MH⁺) 1027 C

499(MH⁺) 1028 C

488(MH⁺) 1029 B

508(MH⁺) 1031 C

502(MH⁺) 1033 C

560(MH⁺) 1034 C

555(MH⁺) 1040 D

474(MH⁺) 1063 C

511(MH⁺) 1069 C

502(MH⁺) 1071 C

488(MH⁺) 1072 C

444(MH⁺) 1080 C

577(MH⁺) 1083 A

637(MH⁺) 1086 C

515(MH⁺) 1088 C

530(MH⁺) 1089 C

472(MH⁺) 1111 C

550(MH⁺) 1112 C

564(MH⁺) 1114 C

564(MH⁺) 1117 C

544(MH⁺) 1118 C

586(MH⁺) 1119 C

518(MH⁺) 1122 B

498(MH⁺) 1123 C

556(MH⁺) 1124 C

546(MH⁺) 1125 C

540(MH⁺) 1126 C

540(MH⁺) 1131 C

585(MH⁺) 1133 C

628(MH⁺) 1134 C

628(MH⁺) 1140 C

600(MH⁺) 1141 C

614(MH⁺) 1142 C

520(MH⁺) 1144 C

568(MH⁺) 1147 C

516(MH⁺) 1150 C

571(MH⁺) 1152 C

522(MH⁺) 1153 C

510(MH⁺) 1156 B

473(MH⁺) 1157 A

442.2(MH⁺) 1158 A

442.2(MH⁺) 1159 A

396.1(MH⁺) 1160 C

541.2(MH⁺) 1161 C

529.2(MH⁺) 1162 C

541.2(MH⁺) 1163 B

529.3(MH⁺) 1164 A

557.3(MH⁺) 1165 A

715.3(MH⁺) 1166 B

581.3(MH⁺) 1167 C

531.2(MH⁺) 1168 A

614.3(MH⁺) 1169 A

614.3(MH⁺) 1170 A

455(MH⁺) 1171 A

559(MH⁺) 1176 C

612(MH⁺) 1178 C

382.1(MH⁺) 1179 C

515.1(MH⁺) 1180 B

379.2(MH⁺) 1181 B

407.3(MH⁺) 1182 B

407.3(MH⁺) 1183 C

407.3(MH⁺) 1184 B

393.2(MH⁺) 1185 B

393.2(MH⁺) 1187 C

527(MH⁺) 1191 A

480.2(MH⁺) 1192 A

508.3(MH⁺) 1193 A

490.4(MH⁺) 1194 A

494.3(MH⁺) 1195 A

494.3(MH⁺) 1196 C

542.3(MH⁺) 1197 A

570.3(MH⁺) 1198 A

552.3(MH⁺) 1199 A

552.3(MH⁺) 1200 A

556.2(MH⁺) 1201 A

556.2(MH⁺) 1202 C

542.3(MH⁺) 1203 A

570.3(MH⁺) 1204 B

570.3(MH⁺) 1205 C

570.3(MH⁺) 1206 A

598.4(MH⁺) 1207 B

570.3(MH⁺) 1208 A

598.4(MH⁺) 1209 C

556.2(MH⁺) 1210 A

556.2(MH⁺) 1211 A

522.3(MH⁺) 1212 A

550.3(MH⁺) 1213 A

522.3(MH⁺) 1214 A

550.3(MH⁺) 1215 A

522.3(MH⁺) 1216 A

550.3(MH⁺) 1217 A

536.3(MH⁺) 1218 A

508.3(MH⁺) 1219 A

536.3(MH⁺) 1220 A

479.3(MH⁺) 1221 A

507.3(MH⁺) 1222 A

507.3(MH⁺) 1223 A

519.3(MH⁺) 1224 A

561.3(MH⁺) 1225 B

561.3(MH⁺) 1226 B

535.4(MH⁺) 1227 A

535.4(MH⁺) 1228 A

519(MH⁺) 1230 C

488(MH⁺) 1231 C

507(MH⁺) 1233 B

497(MH⁺) 1236 B

484.3(MH⁺) 1237 B

458.2(MH⁺) 1238 A

458.2(MH⁺) 1239 C

496.2(MH⁺) 1240 C

542(MH⁺) 1241 C

556(MH⁺) 1242 C

570(MH⁺) 1243 B

553(MH⁺) 1248 C

515(MH⁺) 1250 C

513(MH⁺) 1259 B

506(MH⁺) 1260 C

507(MH⁺) 1261 A

543.2(MH⁺) 1262 A

571.3(MH⁺) 1263 B

571.3(MH⁺) 1264 B

571.3(MH⁺) 1265 C

557.3(MH⁺) 1266 B

557.3(MH⁺) 1267 A

541.3(MH⁺) 1268 A

541.3(MH⁺) 1269 A

541.3(MH⁺) 1270 A

527.3(MH⁺) 1271 A

527.3(MH⁺) 1272 A

513.2(MH⁺) 1273 A

541.3(MH⁺) 1274 A

541.3(MH⁺) 1275 B

527.3(MH⁺) 1276 A

527.3(MH⁺) 1277 C

539.3(MH⁺) 1278 C

567.4(MH⁺) 1279 C

567.4(MH⁺) 1280 C

553.3(MH⁺) 1281 A

553.3(MH⁺) 1282 B

543.2(MH⁺) 1283 A

571.3(MH⁺) 1284 A

571.3(MH⁺) 1285 B

557.3(MH⁺) 1286 A

557.3(MH⁺) 1287 C

513.2(MH⁺) 1288 C

541.3(MH⁺) 1289 C

541.3(MH⁺) 1290 C

541.3(MH⁺) 1291 C

527.3(MH⁺) 1292 A

527.3(MH⁺) 1298 B

566(MH⁺) 1300 B

353(MH⁺) 1301 B

459(MH⁺) 1302 C

473(MH⁺)

TABLE 2

Entry IC₅₀ # μM R¹ R³ m/z 2001 A

500 (MH⁺) 2002 A

500 (MH⁺) 2003 A

485 (MH⁺) 2004 A

484 (MH⁺) 2005 A

502 (MH⁺) 2006 A

421 (MH⁺) 2007 A

471 (MH⁺) 2008 A

501 (MH⁺) 2009 A

517 (MH⁺) 2010 A

441 (MH⁺) 2011 A

459 (MH⁺) 2012 A

513 (MH⁺) 2013 A

511 (MH⁺) 2014 A

455 (MH⁺) 2015 A

485 (MH⁺) 2016 A

379 (MH⁺) 2017 A

435 (MH⁺) 2018 A

431 (MH⁺) 2019 A

423 (MH⁺) 2020 A

409 (MH⁺) 2021 A

409 (MH⁺) 2022 B

457 (MH⁺) 2023 A

499 (MH⁺) 2024 A

393 (MH⁺) 2025 B

459 (MH⁺) 2026 A

672 (MH⁺) 2027 A

520 (MH⁺) 2028 A

530 (MH⁺) 2029 A

546 (MH⁺) 2030 A

620 (MH⁺) 2031 A

544 (MH⁺) 2032 A

494 (MH⁺) 2033 A

530 (MH⁺) 2034 A

478 (MH⁺) 2035 A

558 (MH⁺) 2036 A

572 (MH⁺) 2037 A

492 (MH⁺) 2038 A

554 (MH⁺) 2039 A

646 (MH⁺) 2040 A CH₃

461 (MH⁺) 2041 C

485 (MH⁺) 2042 C

485 (MH⁺) 2043 B

499 (MH⁺) 2044 B

499 (MH⁺) 2045 C

513 (MH⁺) 2046 B

474 (MH⁺) 2047 B

529 (MH⁺) 2048 C

504 (MH⁺) 2049 C

515 (MH⁺) 2050 B

499 (MH⁺) 2051 B

527 (MH⁺) 2054 B

451 (MH⁺) 2055 C

437 (MH⁺) 2056 B

469 (MH⁺) 2057 B

457 (MH⁺) 2058 C

491 (MH⁺) 2059 C

515 (MH⁺) 2060 C

485 (MH⁺) 2061 B

530 2062 B

628 (MH⁺) 2063 C

517 (MH⁺) 2064 C

514 (MH⁺) 2065 C

503 (MH⁺) 2067 C

520 (MH⁺) 2068 B

504 (MH⁺) 2069 C

572 (MH⁺) 2070 B

647 (MH⁺) 2071 C

632 (MH⁺) 2073 B

443 (MH⁺) 2074 B

451 (MH⁺) 2075 C

471 (MH⁺) 2076 B

455 (MH⁺) 2077 B

514 (MH⁺) 2082 B

574 (MH⁺) 2083 A

584 (MH⁺) 2084 C

615 (MH⁺) 2085 C

580 (MH⁺) 2087 C

567 (MH⁺) 2088 A

529 (MH⁺) 2089 C

555 (MH⁺) 2091 C

548 (MH⁺) 2093 C

583 (MH⁺) 2097 C

594 (MH⁺) 2100 C

555 (MH⁺) 2101 C

592 (MH⁺) 2102 C

537 (MH⁺) 2105 C

569 (MH⁺) 2107 C

593 (MH⁺) 2108 A

485 (MH⁺) 2110 C

562.2 (MH⁺) 2111 C CF₃

515.1 (MH⁺) 2112 D

525.3 (MH⁺) 2114 C

539.2 (MH⁺) 2115 B

591.2 (MH⁺) 2116 B

574.2 (MH⁺) 2117 C

574.2 (MH⁺) 2120 C

540.2 (MH⁺) 2121 C

517.2 (MH⁺) 2122 B

538.2 (MH⁺) 2123 C

558.1 (MH⁺) 2125 B

541.2 (MH⁺) 2126 C

527.2 (MH⁺) 2127 D

528.2 (MH⁺) 2128 C

514.1 (MH⁺) 2129 C

930 (MH⁺) 2130 C

900 (MH⁺) 2135 C

484 (MH⁺) 2138 C

591 (MH⁺) 2139 D

523.2 (MH⁺) 2140 D

540.2 (MH⁺) 2141 D

545.1 (MH⁺) 2142 D

513.2 (MH⁺) 2143 D

539.2 (MH⁺)

TABLE 3

Entry IC₅₀ # μM R² R³ m/z 3001 B

520(MH⁺) 3002 D

490(MH⁺) 3005 C

545(MH⁺) 3024 C

527(MH⁺) 3029 C

531(MH⁺) 3033 C

473(MH⁺) 3034 B

605(MH⁺) 3035 C

555(MH⁺) 3037 B

543(MH⁺) 3040 C

472(MH⁺)

TABLE 4

Entry IC₅₀ # μM R¹ R² R³ m/z 4001 D

525(MH⁺)

TABLE 5

Entry IC₅₀ # μM A R⁵ Z R³ m/z 5001 B N H OH — 312(MH⁺) 5002 D N H NHR³

514(MH⁺) 5003 D N H NHR³

630(MH⁺) 5004 C CMe H OH — 325(MH⁺) 5005 D CH H OR³

533(MH⁺) 5006 C CH CH₃ NHR³

527(MH⁺) 5007 D CMe H NHR³

527(MH⁺) 5008 D CMe H NHR³

583(M − H) 5009 C CH CH₃ NHR³

583(M − H)

TABLE 6

Entry IC₅₀ # μM Z m/z 6001 A

424 (MH⁺) 6002 A

424 (MH⁺) 6003 B

570 (MH⁺) 6004 B

526 (MH⁺) 6005 B

525 (MH⁺)

TABLE 7

Entry IC₅₀ # μM R¹ R² m/z 7001 A

336(MH⁺) 7002 A

346(MH⁺) 7003 A

299(MH⁺) 7004 A

311(MH⁺) 7005 A

427(MH⁺) 7006 A

321(MH⁺) 7007 A

365(MH⁺) 7008 A

484(MH⁺) 7009 A

317(MH⁺) 7026 C

327(MH⁺) 7027 B

406(MH⁺) 7010 A

341(MH⁺) 7011 A

347(MH⁺) 7012 A

478(MH⁺) 7013 C

311(MH⁺) 7014 C

379(MH⁺) 7015 C

328(MH⁺) 7016 B

379(MH⁺) 7017 B

464(MH⁺) 7018 C

311(MH⁺) 7019 C

327(MH⁺) 7020 B

406(MH⁺) 7021 C

322(MH⁺) 7022 B

341(MH⁺) 7023 A

327(MH⁺) 7024 C

324(MH⁺) 7025 A

308(MH⁺)

TABLE 8

Entry IC₅₀ # μM R¹ R² R³ m/z 8001 A

487(MH⁺) 8002 B

519(MH⁺) 8003 A

520(MH⁺)

TABLE 9

Entry IC₅₀ # μM R³ m/z 9001 B

499(MH⁺) 9002 B

557(MH⁺)

TABLE 10

IC₅₀ Entry # μM R³ m/z 10001 A

488(MH⁺) 10063 C

511(MH⁺)

TABLE 11

Entry # IC₅₀ R^(3a) R^(3b) R^(3c) R^(3d) m/z 11001 D H OH H H 469 (MH⁺)11002 D

OH H H 513 (MH⁺) 11003 D

H H H 497 (MH⁺) 11004 D

OCH₂COOH H H 497 (MH⁺) 11005 D

OH H H 527 (MH⁺) 11006 D

OH H H 513 (MH⁺) 11007 D

OCH₂COOH CH₂COOH H 629 (MH⁺) 11008 D

OCH₂COOH H H 585 (MH⁺) 11009 D

OCH₂COOH H H 571 (MH⁺) 11010 D

OC(CH₃)₂COOH H H 599 (MH⁺) 11011 D H OCH₂COOH H H 527 (MH⁺) 11012 D HOCH₂COOH CH₂COOH H 585 (MH⁺) 11013 D

OH H H 513 (MH⁺) 11014 D

OCH₂COOH H H 571 (MH⁺) 11015 D

OCH₂COOH H CH₃ 599 (MH⁺) 11016 D

OCH₂COOH CH₃ H 585 (MH⁺) 11017 D

OCH₂COOH CH₃ H 599 (MH⁺) 11018 D

COOH H H 541 (MH⁺) 11019 D

CONH₂ H H 540 (MH⁺) 11020 D

OH H CH₃ 527 (MH⁺) 11021 D

OH CH₃ H 527 (MH⁺) 11022 D

H H 565 (MH⁺) 11023 D

NH₂ H H 512 (MH⁺) 11024 D

NHCOCOOH H H 584 (MH⁺) 11025 D

NHSO₂CH₃ H 590 (MH⁺) 11026 D

NHSO₂CF₃ H H 644 (MH⁺) 11027 D

H H 608 (MH⁺) 11028 D

OH CH₃ H 541 (MH⁺) 11029 D

OC(CH₃)₂COOH CH₃ H 584 (MH⁺) 11030 D

OC(CH₃)₂COOH CH₃ H 613 (MH⁺) 11031 D

H H 786 (MH⁺) 11032 D

OH H H 546 (MH⁺) 11033 D

OH H H 546 (MH⁺)

TABLE 12

Entry # IC₅₀ R¹ R^(3g) R^(3b) m/z 12001 D

CH₃ OH 583 (MH⁺) 12002 D

CH₃ OCH₂COOH 458 (MH⁺) 12003 D

H OCH₂COOH 582 (MH⁺) 12004 D

H OH 567 (MH⁺) 12005 D

H OH 567 (MH⁺) 12006 D

H OH 583 (MH⁺) 12007 D

H OH 513 (MH⁺) 12008 D

H OH 529 (MH⁺) 12009 D

H OH 527 (MH⁺) 12010 D

H OH 583 (MH⁺) 12011 D

H OH 524 (MH⁺) 12012 D

H OH 529 (MH⁺) 12013 D

H OH 523 (MH⁺) 12014 D

H OH 517 (MH⁺) 12015 D

H OH 525 (MH⁺) 12016 D

H OH 540 (MH⁺) 12017 D

H OH 545 (MH⁺) 12018 D

H OH 513 (MH⁺) 12019 D

H OH 539 (MH⁺) 12020 D

H OH 528 (MH⁺) 12021 D

H OCH₂COOH 1057 (MH⁺)  12022 D

H OCH₂COOH 1087 (MH⁺)  12023 D

H OCH₂COOH 599 (MH⁺) 12024 D

H OCH₂COOH 649 (MH⁺) 12025 D

H OCH₂COOH 842 (MH⁺) 12026 D

H OCH₂COOH 905 (MH⁺)

TABLE 13

Entry # IC₅₀ R^(3b) R^(3c) R^(3f) m/z 13001 D OH H H 512 (MH⁺) 13002 DOH CH₃ H 526 (MH⁺) 13003 D OCH₂COOH CH₃ H 584 (MH⁺) 13004 D

H H 607 (MH⁺) 13005 D NH₂ H H 511 (MH⁺) 13006 D NHSO₂CH₃ H H 589 (MH⁺)13007 D NHSO₂CF₃ H H 643 (MH⁺) 13008 D NHCOCOOH H H 583 (MH⁺) 13009 DNHCOCONH₂ H H 582 (MH⁺) 13010 D NHCOCONHCH₃ H H 596 (MH⁺) 13011 DNHCOCONHOH H H 598 (MH⁺) 13012 D

H H 716 (MH⁺) 13013 D NHCOCONH₂ H H 554 (MH⁺) 13014 D OH H CH(CH₂OH)₂586 (MH⁺) 13015 D OH H CH₂CH₂N(CH₃)₂ 583 (MH⁺) 13016 D OH H CH₂CH₂OH 556(MH⁺) 13017 D OH H

625 (MH⁺) 13018 D OH H CH₂CH₂CH₂N(CH₃)₂ 597 (MH⁺) 13019 D OH H

609 (MH⁺) 13020 D OH H

623 (MH⁺) 13021 D OH H C(CH₃)₂CH₂OH 584 (MH⁺) 13022 D OH HCH₂CH(OH)CH₂OH 586 (MH⁺)

TABLE 14

Entry # IC₅₀ R^(3c) R^(3e) m/z 14001 D H CH₃ 566 (MH⁺) 14002 D H NH₂ 567(MH⁺) 14003 D CH₃ NH₂ 581 (MH⁺) 14004 D H NHCH₃ 472 (MH⁺) 14005 D HN(CH₃)₂ 595 (MH⁺) 14006 D H NHCOCH₃ 609 (MH⁺) 14007 D H H 552 (MH⁺)

TABLE 15

Entry # IC₅₀ R¹ m/z 15001 D

563 (MH⁺) 15002 D

562 (MH⁺) 15003 D

551 (MH⁺)

TABLE 16

Entry # IC₅₀ R^(3a) R^(3j) R^(3k) R^(3l) m m/z 16001 D

H OH H 0 460(MH⁺) 16002 D

H CH₂COOH H 1 516(MH⁺) 16003 D

H NH₂ H 1 473(MH⁺) 16004 D

OMe OMe H 0 504(MH⁺) 16005 D H OMe OMe H 0 460(MH⁺) 16006 D

OMe OMe H 0 504(MH⁺) 16007 D

OMe OMe H 1 518(MH⁺) 16008 D

H OH H 1 474(MH⁺) 16009 D

H NHCOCOOH H 1 545(MH⁺) 16010 D

H NHCH₂COOH H 1 531(MH⁺) 16011 D

H OCH₂COOH H 1 532(MH⁺) 16012 D

H COOH H 1 502(MH⁺) 16013 D

H OH H 2 488(MH⁺) 16014 D

H OCH₂COOH H 2 546(MH⁺) 16015 D

OH OH H 1 490(MH⁺) 16016 D

H OCH₂COOH H 0 518(MH⁺) 16017 D

H

H 1 526(MH⁺) 16018 D

H OC(CH₃)₂COOH H 1 560(MH⁺) 16019 D

H

H 1 554(MH⁺) 16020 D

H H OCH₂COOH 1 532(MH⁺) 16021 D

H OH H 1 473(MH⁺) 16022 D

H

H 1 556(MH⁺) 16023 D

H

H 1 525(MH⁺) 16024 D

H

H 1 601(MH⁺) 16025 D

H

H 1 569(MH⁺) 16026 D

H NHCONH₂ H 1 516(MH⁺) 16027 D

H NHCN H 1 512(MH⁺) 16028 D

H NHCHO H 1 501(MH⁺) 16029 D

H

H 1 569(MH⁺) 16030 D

H NHSO₂CF₃ H 1 605(MH⁺) 16031 D

H NHCOCH₃ H 1 515(MH⁺) 16032 D

H NHSO₂CH₃ H 1 551(MH⁺) 16033 D

H

H 1 583(MH⁺) 16034 D

CH₃ OH CH₃ 1 502(MH⁺) 16035 D

H CONH₂ H 1 501(MH⁺) 16036 D

H

H 1 540(MH⁺) 16037 D

H

H 1 540(MH⁺) 16038 D

H CH₂CH₂COOH H 1 530(MH⁺) 16039 D

H

H 1 542(MH⁺) 16040 D

H

H 1 528(MH⁺) 16041 D

Br OH Br 1 632(MH⁺) 16042 D

H O(CH₂)₄COOH H 1 574(MH⁺) 16043 D

H O(CH₂)₃COOH H 1 560(MH⁺) 16044 D

H

H 1 589(MH⁺) 16045 D

H

H 1 589(MH⁺) 16046 D

H OH H 1 550(MH⁺) 16047 D

H OH H 1 564(MH⁺) 16048 D

H OH H 1 558(MH⁺) 16049 D

H

H 1 569(MH⁺) 16050 D

H PO₄ ⁻ H 1 554(MH⁺) 16051 D

OMe H 1 558(MH⁺) 16052 D

OH H 1 518(MH⁺) 16053 D

COOH H H 1 502(MH⁺) 16054 D

COOH OCH₂COOH H 1 576(MH⁺) 16055 D

Cl OCH₂COOH CH₃ 1 581(MH⁺) 16056 D

OH H 1 542(MH⁺) 16057 D

H H 1 526(MH⁺) 16058 D

COOH OH H 1 518(MH⁺) 16059 D

H

H 1 580(MH⁺) 16060 D

H OH H 1 528(MH⁺) 16061 D

H

H 1 540(MH⁺) 16062 D

OH H 1 543(MH⁺) 16063 D

N₃ OCH₂COOH H 1 573(MH⁺) 16064 D

OH H 1 544(MH⁺) 16065 D

OH H 1 546(MH⁺)

TABLE 17

Entry # IC₅₀ μM R¹ R^(3a) R^(3j) R^(3k) R^(3l) m/z 17001 D

OMe OMe H 520(MH⁺) 17002 D

H OMe OMe H 451(MH⁺)

TABLE 18

Entry # IC₅₀ R^(3m) R^(3k) m/z 18001 D

542(MH⁺) 18002 D

542(MH⁺)

TABLE 19

Entry # IC₅₀ R^(3a) R^(3n) A m/z 19001 D

H NCH₂COOH 506(MH⁺) 19002 D

NH₂ S 586(MH⁺)

TABLE 20

Entry # IC₅₀ R^(3k) R^(3p) R^(3r) m/z 20001 D OCH₂COOH CH₃ CH₃ 560(MH⁺)

TABLE 21

Entry # IC₅₀ R^(3o) m/z 21001 D OH 524(MH⁺) 21002 D OCH₂COOH 582(MH⁺)

TABLE 22

Entry IC₅₀ # μM R² R^(3b) R^(3g) m/z 22001 D

OH H 573 (MH⁺) 22002 D

OH H 499 (MH⁺) 22003 D

OH H 529 (MH⁺) 22004 D

OCH₂COOH CH₃ 571 (MH⁺) 22005 D

OCH₂COOH CH₃ 601 (MH⁺) 22006 D

OCH₂COOH H 531 (MH⁺) 22007 D

OCH₂COOH H 557 (MH⁺) 22008 D

OCH₂COOH H 587 (MH⁺) 22009 D

OH H 525 (MH⁺) 22010 D

OH H 541 (MH⁺) 22011 D

OH H 527 (MH⁺) 22012 D

OH H 541 (MH⁺) 22013 D

OH H 525 (MH⁺) 22014 D

OH H 517 (MH⁺) 22015 D

OH H 485 (MH⁺) 22016 D

OH H 527 (MH⁺) 22017 D

OH H 527 (MH⁺) 22018 D

OH H 619 (MH⁺) 22019 D

OH H 543 (MH⁺) 22020 D

OH H 485 (MH⁺) 22021 D

OH H 527 (MH⁺)

1 1 621 PRT Hepatitis C Virus 1 Met Ser Tyr Tyr His His His His His HisAsp Tyr Asp Ile Pro Thr 1 5 10 15 Thr Glu Asn Leu Tyr Phe Gln Gly AlaMet Asp Pro Glu Phe Ser Met 20 25 30 Ser Tyr Thr Trp Thr Gly Ala Leu IleThr Pro Cys Ala Ala Glu Glu 35 40 45 Ser Gln Leu Pro Ile Asn Ala Leu SerAsn Ser Leu Val Arg His Arg 50 55 60 Asn Met Val Tyr Ser Thr Thr Ser ArgSer Ala Ala Leu Arg Gln Lys 65 70 75 80 Lys Val Thr Phe Asp Arg Leu GlnVal Leu Asp Asp His Tyr Arg Asp 85 90 95 Val Leu Lys Glu Met Lys Ala LysAla Ser Thr Val Lys Ala Lys Leu 100 105 110 Leu Ser Val Glu Glu Ala CysLys Leu Thr Pro Pro His Ser Ala Lys 115 120 125 Ser Lys Phe Gly Tyr GlyAla Lys Asp Val Arg Asn Leu Ser Ser Lys 130 135 140 Ala Val Asp His IleArg Ser Val Trp Lys Asp Leu Leu Glu Asp Thr 145 150 155 160 Glu Thr ProIle Asp Thr Thr Ile Met Ala Lys Asn Glu Val Phe Cys 165 170 175 Val GlnPro Glu Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile Val Phe 180 185 190 ProAsp Leu Gly Val Arg Val Cys Glu Lys Met Ala Leu Tyr Asp Val 195 200 205Val Ser Thr Leu Pro Gln Ala Val Met Gly Ser Ser Tyr Gly Phe Gln 210 215220 Tyr Ser Pro Lys Gln Arg Val Glu Phe Leu Val Asn Ala Trp Lys Ser 225230 235 240 Lys Lys Cys Pro Met Gly Phe Ser Tyr Asp Thr Arg Cys Phe AspSer 245 250 255 Thr Val Thr Glu Ser Asp Ile Arg Val Glu Glu Ser Ile TyrGln Cys 260 265 270 Cys Asp Leu Ala Pro Glu Ala Arg Gln Ala Ile Lys SerLeu Thr Glu 275 280 285 Arg Leu Tyr Ile Gly Gly Pro Leu Thr Asn Ser LysGly Gln Asn Cys 290 295 300 Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val LeuThr Thr Ser Cys Gly 305 310 315 320 Asn Thr Leu Thr Cys Tyr Leu Lys AlaSer Ala Ala Cys Arg Ala Ala 325 330 335 Lys Leu Gln Asp Cys Thr Met LeuVal Asn Gly Asp Asp Leu Val Val 340 345 350 Ile Cys Glu Ser Ala Gly ThrGln Glu Asp Ala Ala Asn Leu Arg Val 355 360 365 Phe Thr Glu Ala Met ThrArg Tyr Ser Ala Pro Pro Gly Asp Leu Pro 370 375 380 Gln Pro Glu Tyr AspLeu Glu Leu Ile Thr Ser Cys Ser Ser Asn Val 385 390 395 400 Ser Val AlaHis Asp Ala Ser Gly Lys Arg Val Tyr Tyr Leu Thr Arg 405 410 415 Asp ProThr Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala Arg His 420 425 430 ThrPro Ile Asn Ser Trp Leu Gly Asn Ile Ile Met Tyr Ala Pro Thr 435 440 445Leu Trp Ala Arg Met Val Leu Met Thr His Phe Phe Ser Ile Leu Leu 450 455460 Ala Gln Glu Gln Leu Glu Lys Ala Leu Asp Cys Gln Ile Tyr Gly Ala 465470 475 480 Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Gln Ile Ile Glu ArgLeu 485 490 495 His Gly Leu Ser Ala Phe Ser Leu His Ser Tyr Ser Pro GlyGlu Ile 500 505 510 Asn Arg Val Ala Ser Cys Leu Arg Lys Leu Gly Val ProPro Leu Arg 515 520 525 Val Trp Arg His Arg Ala Arg Ser Val Arg Ala LysLeu Leu Ser Gln 530 535 540 Gly Gly Arg Ala Ala Thr Cys Gly Lys Tyr LeuPhe Asn Trp Ala Val 545 550 555 560 Arg Thr Lys Leu Lys Leu Thr Pro IlePro Ala Ala Ser Arg Leu Asp 565 570 575 Leu Ser Gly Trp Phe Val Ala GlyTyr Asn Gly Gly Asp Ile Tyr His 580 585 590 Ser Leu Ser Arg Ala Arg ProArg Trp Phe Met Leu Cys Leu Leu Leu 595 600 605 Leu Ser Val Gly Val GlyIle Tyr Leu Leu Pro Asn Arg 610 615 620

What is claimed is:
 1. A compound of formula I:

wherein: X is CH and A is N; or X is N and A is COR⁷ or CR⁵, wherein R⁵is H, halogen, or (C₁₋₆) alkyl and R⁷ is H or (C₁₋₆ alkyl); Y is O or S;Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from: COOHand —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; R⁶ is H, halogen, (C₁₋₆ alkyl) orOR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ is selected from the groupconsisting of 5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl,phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃, 9- or10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂; R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, -CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is aninteger from 1 to 4; —CONH(C₆₋₁₀) aryl-5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH,wherein p is an integer from 1 to 4; —O(CH₂)_(p)tetrazolyl, wherein p isan integer from 1 to 4; and n is zero or 1; or a detectable derivativeor salt thereof; wherein the detectable derivative is selected from acompound of the formula (I) labeled with a fluorescent label or acolorimetric label; with the proviso that if X is CH, Y is O, Z is OH,n=0, and R² is alkyl or hydroxyalkyl, then R¹ is not a five memberedheterocycle containing S and N; and with the further proviso that if Xis CH, Y is O, Z is OH, n=0, and R¹ is (C₂₋₁₀)alkyl, (C₃₋₁₀)alkenyl,(C₃₋₆)cycloalkyl or phenyl, then R² is not phenyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkyl orhydroxyalkyl, then R¹ is not 5-nitro-2-furyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=0, and R² is optionallysubstituted alkyl or cycloalkyl, then R¹ is 5-aryl-2-furyl; and with thefurther proviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkylor cycloalkyl, then R¹ is not 6-phenylbenzofuran-2-yl; and with thefurther proviso that if X is CH, Y is O, Z is OH, n=0, and R² is n-Pr,then R¹ is not 2,3-benzofuranyl or phenyl; and with the further provisothat if X is CH, Y is O, Z is OH, n=0, and R² is Me, then R¹ is notphenyl or methoxy-2,3-benzofuranyl; and with the further proviso that ifX is CH, Y is O, Z is OH, n=0, and R² is Et, then R¹ is notmethoxy-2,3-benzofuranyl; and with the further proviso that if X is CH,Y is O, Z is OH, n=0, and R² is (C₁₋₈)alkyl, then R¹ is not ethenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is lower alkyl, then R¹ is not substituted or unsubstituted phenyl,heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is lower alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not alkenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is alkyl, then R¹ is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl, then R¹ is not (C₅₋₁₅)aryl,(C₂₋₆)alkenyl or (C₃₋₁₀)heteroarylene; and with the further proviso thatif X is CH, Y is O, Z is OH, n=0, and R² is (C₁₋₂)alkyl, then R¹ is notphenyl or aryl; and with the further proviso that if X is CH, Y is O, Zis OH, n=0, and R² is alkyl or cycloalkyl, then R¹ is not2-hydroxyphenyl; and with the further proviso that if X is CH, Y is O, Zis OH, n=1, then R¹ is not methyl, ethyl or vinyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=1, then R¹ is not5-azabenzimidazol-2-yl; and with the further proviso that if X is CH, Yis O, Z is OH, n=0 or 1, and R² is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkylthen R¹ is not C₁₋₄alkyl optionally substituted by OH, COOH or halo; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, R¹is heteroaryl or phenyl, then R² is not heteroaryl or phenyl; and withthe further proviso that if X is CH, Y is O, Z is NHR³ wherein R³ is(C₁₋₃)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, andfurther substituted with aryl or heteroaryl, n=0 or 1, and R¹ is(C₂₋₁₀)alkyl, (C₃₋₆)cycloalkyl or phenyl, then R² is not optionallysubstituted phenyl; and with the further proviso that if X is CH, Y isO, Z is NMeR³ or NHR³ (wherein R³ is alkyl), n=0, and R² is alkyl,cycloalkyl or aryl, then R¹ is not a substituted 2-benzofuryl group; andwith the further proviso that if X is CH, Y is O, Z is NHR³ wherein R³is alkyl, n=0, and R² is alkyl or cycloalkyl, then R¹ is not asubstituted benzofuryl group or benzofuran-2-yl; and with the furtherproviso that if X is CH, Y is O, Z is NHR³ wherein R³ is Me, n=0, and R²is Me, then R¹ is not methoxy-2,3-benzofuranyl; and with the provisothat if X is CH, Y is O, Z is NHR³ (wherein R³ is alkyl or aryl), n=0,and R² is alkyl not substituted with OH, then R¹ is not aryl orheterocycle; and with the further proviso that if X is CH, Y is O, Z isNHR³ (wherein R³ is alkyl, cycloalkyl, aryl or heteroaryl), n=0, and R²is alkyl or cycloalkyl, then R¹ is not aryl, heteroaryl or alkyl; andwith the further proviso that if X is CH, Y is O, Z is OH or NHR³ orNMeR³ (wherein R³ is (C₁₋₄)alkyl), n=0, and R² is (C₁₋₄)alkyl, then R¹is not phenyl bearing an N-substituted sulfonamido group; and with thefurther proviso that if X is CH, Y is O, Z is OH or NHR³ wherein R³ isalkyl, cycloalkyl, aryl or heterocycle, n=0, and R² is alkyl orcycloalkyl, then R¹ is not 3,4-dialkoxyphenyl,3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene; and with thefurther proviso that if X is CH, Y is O, Z is OH or NHR³ wherein R³ isH, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl, n=0, andR² is alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not tetrazolyl; andwith the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl,arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl,n=0, and R² is lower alkyl, then R¹ is not substituted phenyl orheteroaryl; and with the further proviso that if X is CH, Y is O, Z isOH or NHR³ wherein R³ is H, alkyl, phenyl or benzyl, n=0, and R² is(C₁₋₄)alkyl, then R¹ is not phenyl; and with the further proviso that ifX is CH, Y is O, Z is OH or NH₂, n=0, and R² is alkyl or hydroxyalkyl,then R¹ is not fluoroalkyl; and with the further proviso that if X isCH, Y is O, Z is OH or NH₂, n=0, and R² is alkyl, then R¹ is not alkenylor aryl; and with the further proviso that if X is CH, Y is O, Z is NHR³(wherein R³ is thiazolyl), n=1, and R² is (C₁₋₈)alkyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, phenyl or heteroaryl, then R¹ is not phenyl,phenyl(C₂₋₄)alkenyl, heteroaryl, heterocycle, (C₁₋₈)alkyl,(C₂₋₆)alkenyl, or (C₃₋₇)cycloalkyl; and with the further proviso that ifX is CH, Y is O, Z is OH or NH₂, n=1, and R² is (C₁₋₅)alkyl, then R¹ isnot methyl or optionally halogenated phenyl; and with the furtherproviso that if X is CH, Y is O, Z is NH₂, n=0, and R² is n-Pr, then R¹is not phenylethenyl; and with the further proviso that if X is CH, Y isO, Z is NH₂, n=0, and R² is alkyl, then R¹ is not substituted phenyl ornaphthyl; and with the further proviso that if X is CH, Y is O, Z is NH₂or NHR³ wherein R³ is (C₁₋₄)alkyl, benzyl or p-fluorophenylmethyl, n=0,and R² is (C₁₋₄)alkyl, then R¹ is not phenyl substituted with acylamino;and with the proviso that when n=0 and Y=O, then Z is not OH or OR³,wherein R³ is H, (C₁₋₆)alkyl or (C₆₋₁₀)aryl(C₁₋₆)alkyl, wherein saidalkyl and said aryl are optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₁₋₆)alkyl-hydroxy, halogen,(C₁₋₆)alkylamino, di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl and(CH₂)_(p)COOH in which p is an integer from 1 to 4; and with the provisothat when n=0 and Y=O, then Z is not OR³ wherein R³ is(C₆₋₁₀)aryl(C₁₋₆)alkyl, optionally substituted with from 1 to 4substituents selected from the group consisting of: cyano, NO₂, —COCH₃,—CONH₂, —NH₂, sulfonamido, —SO₂CH₃, —NHSO₂CH₃ and (C₁₋₄)alkoxy; and withthe proviso that when n=0 and Y=O, then Z is not NH₂, NMeR³ or NHR³,wherein R³ is H, or (C₁₋₆)alkyl optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino and di-(C₁₋₆)alkyl-amino; andwith the proviso that when n=1 and Y=O, then Z is not OH or OR³ whereinR³ is (C₁₋₆)alkyl.
 2. A compound of formula Ia:

wherein: X is N; Y is O or S; Z is OH, NH₂, NMeR³ or NHR³; and whereinR¹ is selected from 5- or 6-membered heteroaryl or heterocycle having 1to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl,(C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, 9- or10-atom heterobicycle having 1 to 4 heteroatoms selected from O, N andS, wherein said heteroaryl, phenyl, phenylalkenyl, phenylalkyl, alkenyl,cycloalkyl, (C₁₋₆)alkyl, and heterobicycle are all optionallysubstituted with 1 to 4 substituents selected from: OH, halogen, cyano,phenyl(C₁₋₄)alkoxy, COOH, —OCH₂CONHCH₂Ph, (C₁₋₄)alkyl,—OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy, —OCH₂CO-(morpholino),pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy, —NH(C₂₋₄)acyl,—O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃ and NO₂; R² isselected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from: halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,and 5- to 10-membered heterocycle having 1 to 4 heteroatoms selectedfrom O, N and S; wherein said alkyl, cycloalkyl, aryl, alkenyl andheterocycle are all optionally substituted with from 1 to 4 substituentsselected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, phenyl, benzyloxy,halogen, (C₂₋₄)alkenyl, carboxy(C₂₋₄)alkenyl, 5- to 6-memberedheterocycle having 1 to 4 heteroatoms selected from O, N and S, saidheterocycle being optionally substituted with from 1 to foursubstituents selected from: CH₃, CF₃, OH, CH₂COOH and COOH; 9- to10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S said heterobicycle being optionally substituted with from 1 to 4substituents selected from: halogen, (C₁₋₃)alkyl, (C₁₋₃)alkoxy,tetrazolyl, COOH, —CONH₂, triazolyl, OH, and —O(C₁₋₃)alkylCOOH;(C₁₋₄)alkoxy, cyano, amino, azido, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, nitro, C(halo)₃,NH(C₂₋₄)acyl, —NHCOCOOH, —NHCH₂COOH, —NHCONH₂,

 —NHCN, —NHCHO, —NHSO₂CH₃, —NHSO₂CF₃, —NH(C₆₋₁₀)aroyl, —CONH₂,—CO—NH-alanyl, —(CH₂)_(p)COOH, —OCH₂Ph, —O—(C₁₋₆)alkyl COOH,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(CH₃)₂, —CONH(C₂₋₄)alkylmorpholino and—O(CH₂)_(p)tetrazolyl, p being an integer from 1 to 4; and n is zero or1; or a salt thereof; with the proviso that if X is CH, Y is O, Z is OH,n=0, and R² is alkyl or hydroxyalkyl, then R¹ is not a five memberedheterocycle containing S and N; and with the further proviso that if Xis CH, Y is O, Z is OH, n=0, and R¹ is (C₂₋₁₀)alkyl, (C₃₋₁₀)alkenyl,(C₃₋₆)cycloalkyl or phenyl, then R² is not phenyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkyl orhydroxyalkyl, then R¹ is not 5-nitro-2-furyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=0, and R² is optionallysubstituted alkyl or cycloalkyl, then R¹ is 5-aryl-2-furyl; and with thefurther proviso that if X is CH, Y is O, Z is OH, n=0, and R² is alkylor cycloalkyl, then R¹ is not 6-phenylbenzofuran-2-yl; and with thefurther proviso that if X is CH, Y is O, Z is OH, n=0, and R² is n-Pr,then R¹ is not 2,3-benzofuranyl or phenyl; and with the further provisothat if X is CH, Y is O, Z is OH, n=0, and R² is Me, then R¹ is notphenyl or methoxy-2,3-benzofuranyl; and with the farther proviso that ifX is CH, Y is O, Z is OH, n=0, and R² is Et, then R¹ is notmethoxy-2,3-benzofuranyl; and with the further proviso that if X is CH,Y is O, Z is OH, n=0, and R² is (C₁₋₈)alkyl, then R¹ is not ethenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is lower alkyl, then R¹ is not substituted or unsubstituted phenyl,heteroaryl, CHCHphenyl, CHCHfuryl, CHCHpyridyl or CHCHquinolinyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is lower alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not alkenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is alkyl, then R¹ is not aryl, pyridyl, 2-hydroxyphenyl or alkenyl; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0, and R²is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkyl, then R¹ is not (C₅₋₁₅)aryl,(C₂₋₆)alkenyl or (C₃₋₁₀)heteroarylene; and with the further proviso thatif X is CH, Y is O, Z is OH, n=0, and R² is (C₁₋₁₂)alkyl, then R¹ is notphenyl or aryl; and with the further proviso that if X is CH, Y is O, Zis OH, n=0, and R² is alkyl or cycloalkyl, then R¹ is not2-hydroxyphenyl; and with the further proviso that if X is CH, Y is O, Zis OH, n=1, then R¹ is not methyl, ethyl or vinyl; and with the furtherproviso that if X is CH, Y is O, Z is OH, n=1, then R¹ is not5-azabenzimidazol-2-yl; and with the further proviso that if X is CH, Yis O, Z is OH, n=0 or 1, and R² is (C₁₋₄)alkyl or hydroxy(C₁₋₄)alkylthen R¹ is not C₁₋₄alkyl optionally substituted by OH, COOH or halo; andwith the further proviso that if X is CH, Y is O, Z is OH, n=0 or 1, R¹is heteroaryl or phenyl, then R² is not heteroaryl or phenyl; and withthe further proviso that if X is CH, Y is O, Z is NHR³ wherein R³ is(C₁₋₃)alkyl, substituted with COOH, COOalkyl or tetrazol-5-yl, andfurther substituted with aryl or heteroaryl, n=0 or 1, and R¹ is(C₂₋₁₀)alkyl, (C₃₋₆)cycloalkyl or phenyl, then R² is not optionallysubstituted phenyl; and with the further proviso that if X is CH, Y isO, Z is NMeR³ or NHR³ (wherein R³ is alkyl), n=0, and R² is alkyl,cycloalkyl or aryl, then R¹ is not a substituted 2-benzofuryl group; andwith the further proviso that if X is CH, Y is O, Z is NHR³ wherein R³is alkyl, n=0, and R² is alkyl or cycloalkyl, then R¹ is not asubstituted benzofuryl group or benzofuran-2-yl; and with the furtherproviso that if X is CH, Y is O, Z is NHR³ wherein R³ is Me, n=0, and R²is Me, then R¹ is not methoxy-2,3-benzofuranyl; and with the provisothat if X is CH, Y is O, Z is NHR³ (wherein R³ is alkyl or aryl), n=0,and R² is alkyl not substituted with OH, then R¹ is not aryl orheterocycle; and with the further proviso that if X is CH, Y is O, Z isNHR³ (wherein R³ is alkyl, cycloalkyl, aryl or heteroaryl), n=0, and R²is alkyl or cycloalkyl, then R¹ is not aryl, heteroaryl or alkyl; andwith the further proviso that if X is CH, Y is O, Z is OH or NHR³ orNMeR³ (wherein R³ is (C₁₋₄)alkyl), n=0, and R² is (C₁₋₄)alkyl, then R¹is not phenyl bearing an N-substituted sulfonamido group; and with thefurther proviso that if X is CH, Y is O, Z is OH or NHR³ wherein R³ isalkyl, cycloalkyl, aryl or heterocycle, n=0, and R² is alkyl orcycloalkyl, then R¹ is not 3,4-dialkoxyphenyl,3,4-dialkoxyphenylphenylene or 3,4-dialkoxyphenylalkylene; and with thefurther proviso that if X is CH, Y is O, Z is OH or NHR³ wherein R³ isH, alkyl, allyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl, n=0, andR² is alkyl, cycloalkyl or hydroxyalkyl, then R¹ is not tetrazolyl; andwith the further proviso that if X is CH, Y is O, Z is OH or NHR³wherein R³ is alkyl, halogenoalkyl, alkoxyalkyl, alkylcarbonyl,arylcarbonyl, arylsulphonyl, arylaminocarbonyl or arylmethylsulphonyl,n=0, and R² is lower alkyl, then R¹ is not substituted phenyl orheteroaryl; and with the further proviso that if X is CH, Y is O, Z isOH or NHR³ wherein R³ is H, alkyl, phenyl or benzyl, n=0, and R² is(C₁₋₄)alkyl, then R¹ is not phenyl; and with the further proviso that ifX is CH, Y is O, Z is OH or NH₂, n=0, and R² is alkyl or hydroxyalkyl,then R¹ is not fluoroalkyl; and with the further proviso that if X isCH, Y is O, Z is OH or NH₂, n=0, and R² is alkyl, then R¹ is not alkenylor aryl; and with the further proviso that if X is CH, Y is O, Z is NHR³(wherein R³ is thiazolyl), n=1, and R² is (C₁₋₈)alkyl, (C₁₋₆)haloalkyl,(C₃₋₇)cycloalkyl, phenyl or heteroaryl, then R¹ is not phenyl,phenyl(C₂₋₄)alkenyl, heteroaryl, heterocycle, (C₁₋₈)alkyl,(C₂₋₆)alkenyl, or (C₃₋₇)cycloalkyl; and with the further proviso that ifX is CH, Y is O, Z is OH or NH₂, n=1, and R² is (C₁₋₅)alkyl, then R¹ isnot methyl or optionally halogenated phenyl; and with the furtherproviso that if X is CH, Y is O, Z is NH₂, n=0, and R² is n-Pr, then R¹is not phenylethenyl; and with the further proviso that if X is CH, Y isO, Z is NH₂, n=0, and R² is alkyl, then R¹ is not substituted phenyl ornaphthyl; and with the further proviso that if X is CH, Y is O, Z is NH₂or NHR³ wherein R³ is (C₁₋₄)alkyl, benzyl or p-fluorophenylmethyl, n=0,and R² is (C₁₋₄)alkyl, then R¹ is not phenyl substituted with acylamino;and with the proviso that when n=0 and Y=O, then Z is not OH; and withthe proviso that when n=0 and Y=O, then Z is not NH₂, NMeR³ or NHR³,wherein R³ is H, or (C₁₋₆)alkyl optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino and di-(C₁₋₆)alkyl-amino; andwith the proviso that when n=1 and Y=O, then Z is not OH.
 3. A compoundof formula I as claimed in claim 1, having the following formula:

wherein R¹ is selected from the group consisting of 5- or 6-memberedheterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl,phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₁₋₆)alkyl, CF₃, 9- or 10-membered heterobicycle having 1 to 4heteroatoms selected from O, N and S, wherein said heterocycle, phenyl,phenyl(C₂₋₆)alkenyl and phenyl(C₁₋₃)alkyl, alkenyl, cycloalkyl,(C₁₋₆)alkyl, and heterobicycle are all optionally substituted with from1 to 4 substituents selected from: OH, halogen, CF₃, amino, cyano,phenyl(C₁₋₄)alkoxy, COOH, —OCH₂CONHCH₂Ph, (C₁₋₄)alkyl,—OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy, —OCH₂CO-(morpholino),pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy, —NH(C₂₋₄)acyl,—O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, and NO₂; R² isselected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH, —NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl-(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from; COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH; —CONH(C₆₋₁₀) aryl-5-or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, said heterocycle being optionally substituted with from 1 to 4substituents selected from: COOH and (CH₂)_(p)COOH;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH;—O(CH₂)_(p)tetrazolyl; and n is zero or 1; wherein p is an integer from1 to 4; or a detectable derivative or salt thereof; wherein thedetectable derivative is selected from a compound of the formula (I)labeled with a fluorescent label or a colorimetric label.
 4. A compoundof formula I as claimed in claim 1, having the following formula:

wherein Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle,having 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; A is N, R⁶ is H,halogen, (C₁₋₆ alkyl) or OR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ isselected from the group consisting of 5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N, and S, phenyl,phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₁₋₆)alkyl, CF₃, 9- or 10-membered heterobicycle having 1 to 4heteroatoms selected from O, N and S, wherein said heterocycle, phenyl,phenyl(C₂₋₆)alkenyl and phenyl(C₁₋₃)alkyl, alkenyl, cycloalkyl,(C₁₋₆)alkyl, and heterobicycle are all optionally substituted with from1 to 4 substituents selected from: OH, halogen, CF₃, amino, cyano,phenyl(C₁₋₄)alkoxy, COOH, —OCH₂CONHCH₂Ph, (C₁₋₄)alkyl,—OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy, —OCH₂CO-(morpholino),pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy, —NH(C₂₋₄)acyl,—O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, and NO₂; R² isselected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl-(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from; COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH; —CONH(C₆₋₁₀) aryl-5-or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, said heterocycle being optionally substituted with from 1 to 4substituents selected from: COOH and (CH₂)_(p)COOH;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH;—O(CH₂)_(p)tetrazolyl; and n is zero or 1; wherein p is an integer from1 to 4; or a detectable derivative or salt thereof; wherein thedetectable derivative is selected from a compound of the formula (I)labeled with a fluorescent label or a calorimetric label.
 5. A compoundof formula I as claimed in claim 4, wherein R⁶ is H or (C₁₋₆)alkyl.
 6. Acompound of formula I as claimed in claim 5, wherein R⁶ is H.
 7. Acompound of formula I as claimed in claim 4, wherein Z is NHR³, OR³, orOH.
 8. A compound of formula I as claimed in claim 7, wherein Z is NHR³.9. A compound of formula I as claimed in claim 1, wherein R¹ is selectedfrom the group consisting of 5- or 6-membered heterocycle having 1 to 4heteroatoms selected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl,(C₂₋₆)alkenyl, phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃,9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected fromO, N and S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl, alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrole, pyrrolidinyl, carboxy(C₂₋₄)alkenyl,phenoxy, —NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4,SO₃H, and NO₂.
 10. A compound of formula I as claimed in claim 9,wherein R¹ is furanyl, tetrahydrofuranyl, pyridyl, N-methylpyrrolyl,pyrrolidinyl, pyrazine, imidazole, isoquinoline, thiazole, thiadiazole,pyrazole, isoxazole, indole, thiophenyl, 1,3-benzodioxazole,1,4-benzodioxan, CF₃, or phenyl; wherein said furanyl,tetrahydrofuranyl, pyridyl, N-methylpyrrolyl, pyrazine, isoquinoline,thiazole, pyrazole, isoxazole, indole, thiophenyl, 1,3-benzodioxazole,1,4-benzodioxan or phenyl being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆alkyl), (C₁₋₄)alkoxy,—OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, COOH, OH, halogen, CF₃, cyano, phenoxy,pyrrolidinyl, —NH(C₂₋₄)acyl, —O(CH₂)₂OH, NO₂, SO₃H,


11. A compound of formula I as claimed in claim 10, wherein R¹ isfuranyl, pyridinyl, pyridyl, phenyl, thiophenyl, thiadiazole,1,3-benzodioxazole, pyrazine, imidazole, pyrazole, or isooxazole,wherein said furanyl, pyridyl, pyridinyl, phenyl, thiophene,thiadiazole, 1,3-benzodioxazole, pyrazine, imidazole, pyrazole,isooxazole being optionally substituted with from 1 to 4 substituentsselected from: (C₁₋₆alkyl), halogen, CF₃, OH, —O(CH₂)₂OH,


12. A compound of formula I as claimed in claim 11, wherein R¹ isfuranyl, pyridinyl, thiophenyl or phenyl.
 13. A compound of formula I asclaimed in claim 1, wherein R² is selected from (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl,norbornane, phenyl, and pyridyl, all of which is optionally substitutedwith from 1 to 4 substituents selected from: halogen, (C₁₋₆)alkyl,—CH₂OH, O-benzyl and OH.
 14. A compound of formula I as claimed in claim13, wherein R² is (C₁₋₆ alkyl), norbornane, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl,


15. A compound of formula I as claimed in claim 14, wherein R² iscyclohexyl.
 16. A compound of formula I as claimed in claim 1, whereinR³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCH, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl-(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from; COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH; —CONH(C₆₋₁₀) aryl-5-or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, said heterocycle being optionally substituted with from 1 to 4substituents selected from: COOH and (CH₂)_(p)COOH;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH; and—O(CH₂)_(p)tetrazolyl; wherein p is an integer from 1 to 4; or adetectable salt or derivative thereof; wherein the detectable derivativeis selected from a compound of the formula (I) labeled with afluorescent label or a colorimetric label.
 17. A compound of formula Ias claimed in claim 16, wherein R³ is

wherein R^(3a) is selected from H, 5- to 10-atom heterocycle having 1 to4 heteroatoms selected from O, N and S; COOH, COO(C₁₋₆)alkyl, saidheterocycle being optionally substituted with from 1 to 4 substituentsselected from the group consisting of: CH₃, CF₃, OH, CH₂COOH, COOH,NHCH(CH₃)₂, NHCOCH₃, NH₂, NHCH₃, N(CH₃)₂, —CONH₂, —COCH₃ —(CH₂)_(p)COOH,—OCH₂Ph, —CH₂(C₆₋₁₀)aryl-COOH, —CONHpyridyl, —CONHCH₂pyridyl, and—CONH(C₂₋₄)alkylN(CH₃)₂; R^(3b) is selected from H, OH, OCH₂OH, amino,5- to 10-atom heterocycle having 1 to 4 heteroatoms selected from O, Nand S; said heterocycle being optionally substituted with OH, COOH, CH₃,CF₃, CH₂COOH, —O(C₁₋₃)alkylCOOH, —NHCOCOOH, —NHSO₂CH₃, —NHSO₂CF₃,

 R^(3c) is selected from H, (C₁₋₆)alkyl or —(CH₂)_(p)COOH, wherein p isan integer from 1 to 4; and R^(3d) is H or (C₁₋₆ alkyl).
 18. A compoundof formula I as claimed in claim 17, wherein R^(3a) is COOR^(3g),CONHR^(3f), or

wherein R^(3e) is H, (C₁₋₆ alkyl), amino, NH(C₁₋₆alkyl), N{(C₁₋₆alkyl)}₂, or NHCO(C₁₋₆ alkyl); R^(3f) is H, —(C₂₋₄) alkyl-morpholino,—(C₂₋₄) alkyl-pyrrolidino, —(C₂₋₄) alkyl-N-methylpyrrolidino; (C₁₋₆alkyl)N(CH₃)₂, (C₁₋₆ alkyl)OH, CH(CH₂OH)₂ or CH₂C(OH)CH₂OH; and R^(3g)is H or (C₁₋₆ alkyl).
 19. A compound of formula I as claimed in claim18, wherein R^(3f) is H.
 20. A compound of formula I as claimed in claim18, wherein R^(3g) is H or CH₃.
 21. A compound of formula I as claimedin claim 17, wherein R^(3b) is OCH₂OH or OH.
 22. A compound of formula Ias claimed in claim 17 wherein R^(3c) is H, CH₃ or —CH₂CH₂COOH.
 23. Acompound of formula I as claimed in claim 17, wherein R^(3d) is H orCH₃.
 24. A compound of formula I as claimed in claim 23, wherein R^(3d)is H.
 25. A compound of formula I as claimed in claim 16, wherein R³ is:

wherein R^(3a) is as defined in claim 20 above; R^(3j) is (C₁₋₄)alkoxy,OH, O(C₁₋₆ alkyl)COOH, (C₁₋₆ alkyl),halogen; (C₂₋₆)alkenylCOOH,(C₁₋₆)alkyl-hydroxy, COOH, or azido; R^(3k) is OH, (CH₂)_(p)COOH where pis an integer from 1 to 4, amino, (C₁₋₄)alkoxy, NHCOCOOH, NH(C₁₋₆alkyl)COOH, O(C₁₋₆ alkyl)COOH, COOH, 5- or 6-membered heterocycle having1 to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from thegroup consisting of: CH₃, CF₃, OH, CH₂COOH, COOH; —O—(C₁₋₆)alkyl COOH,

 NHCONH₂, NHCN, NHCHO, NHSO₂CF₃, NHCOCH₃, NHSO₂CH₃, CONH₂,(C₃₋₆)cycloalkylCOOH, (C₂₋₆)alkenylCOOH, and NHCOCH(OH)COOH; R^(3l) isO(C₁₋₆ alkyl)COOH, (C₁₋₆ alkyl), or halogen; and m is an integer from 0to
 4. 26. A compound of formula I as claimed in claim 25, wherein mis
 1. 27. A compound of formula I as claimed in claim 16, wherein R³ is:

wherein R^(3k) is OH, (CH₂)_(p)COOH where p is an integer from 1 to 4,amino, (C₁₋₄)alkoxy, NHCOCOOH, NH(C₁₋₆ alkyl)COOH, O(C₁₋₆ alkyl)COOH,COOH, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selectedfrom O, N and S, said heterocycle being optionally substituted with from1 to 4 substituents selected from the group consisting of: CH₃, CF₃, OH,CH₂COOH, COOH, NCH(CH₃)₂, NCOCH₃, NH₂, NHCH₃, and N(CH₃)₂;—O—(C₁₋₆)alkyl COOH,

 NHCONH₂, NHCN, NHCHO, NHSO₂CF₃, NHCOCH₃, NHSO₂CH₃, CONH₂,(C₃₋₆)cycloalkylCOOH, (C₂₋₆)alkenylCOOH, and NHCOCH(OH)COOH R^(3m) is Hor OH; R^(3p) is H, halogen, or (C₁₋₆alkyl); and R^(3r) is H, halogen,or (C₁₋₆ alkyl).
 28. A compound of formula I as claimed in claim 16,wherein R³ is

wherein R^(3o) is OH or O(C₁₋₆ alkyl)COOH.
 29. A compound of formula Ias claimed in claim 16, wherein R³ is:

wherein R^(3a) is selected from H, 5- or 10-atom heterocycle having 1 to4 heteroatoms selected from O, N and S; COOH, COO(C₁₋₆)alkyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from the group consisting of: CH₃, CF₃, OH,CH₂COOH, COOH, NCH(CH₃)₂, NCOCH₃, NH₂, NHCH₃, N(CH₃)₂, —CONH₂, —COCH₃,—COCH₃ —(CH₂)_(p)COOH, —OCH₂Ph, —CH₂(C₆₋₁₀)aryl-COOH, —CONHpyridyl,—CONHCH₂pyridyl, and —CONH(C₂₋₄)alkylN(CH₃)₂; J is S or N(C₁₋₆ alkyl);and R^(3n) is H or amino.
 30. A compound of formula I as claimed inclaim 29, wherein J is S or N(CH₃).
 31. A pharmaceutical compositioncomprising a compound of the formula I, as claimed in claim 1, or apharmaceutically acceptable salt thereof, as an inhibitor of RNAdependent RNA polymerase activity of the enzyme NS5B encoded by HCV. 32.A pharmaceutical composition comprising a compound of the formula I, asclaimed in claim 1, or a pharmaceutically acceptable salt thereof, as aninhibitor of HCV replication.
 33. A method of treating or preventing HCVinfection in a mammal, comprising administering to the mammal aneffective amount of a compound of the following formula I, or apharmaceutically acceptable salt thereof:

wherein: X is CH and A is N; or X is N and A is COR⁷ or CR⁵, wherein R⁵is H, halogen, or (C₁₋₆) alkyl and R⁷ is H or (C₁₋₆ alkyl); Y is O or S;Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from: COOHand —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; R⁶ is H, halogen, (C₁₋₆ alkyl) orOR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ is selected from the groupconsisting of 5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl,phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃, 9- or10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₆)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂; R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is aninteger from 1 to 4; —CONH(C₆₋₁₀) aryl-5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH,wherein p is an integer from 1 to 4; —O(CH₂)_(p)tetrazolyl, wherein p isan integer from 1 to 4; and n is zero or 1; and with the proviso thatwhen n=0 and Y=O, then Z is not OH or OR³, wherein R³ is H, (C₁₋₆)alkylor (C₆₋₁₀)aryl(C₁₋₆)alkyl, wherein said alkyl and said aryl areoptionally substituted with from 1 to 4 substituents selected from thegroup consisting of: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, halogen, (C₁₋₆)alkylamino, di-(C₁₋₆)alkyl-amino,C(halogen)₃, —NH(C₂₋₄)acyl and (CH₂)_(p)COOH in which p is an integerfrom 1 to 4; and with the proviso that when n=0 and Y=O, then Z is notOR³ wherein R³ is(C₆₋₁₀)aryl(C₁₋₆)alkyl, optionally substituted withfrom 1 to 4 substituents selected from the group consisting of: cyano,NO₂, —COCH₃, —CONH₂, —NH₂, sulfonamido, —SO₂CH₃, —NHSO₂CH₃ and(C₁₋₄)alkoxy; and with the proviso that when n=0 and Y=O, then Z is notNH₂, NMeR³ or NHR³, wherein R³ is H, or (C₁₋₆)alkyl optionallysubstituted with from 1 to 4 substituents selected from the groupconsisting of: OH, COOH, COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino anddi-(C₁₋₆)alkyl-amino; and with the proviso that when n=1 and Y=O, then Zis not OH or OR³ wherein R³ is (C₁₋₆)alkyl.
 34. A pharmaceuticalcomposition for the treatment or prevention of HCV infection, comprisingan effective amount of a compound of formula I, as claimed in claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 35. A method of inhibiting the RNA dependent RNApolymerase activity of the enzyme NS5B encoded by HCV, comprisingcontacting said enzyme with a compound of the following formula I or apharmaceutically acceptable salt thereof:

wherein: X is CH and A is N; or X is N and A is COR⁷ or CR⁵, wherein R⁵is H, halogen, or (C₁₋₆) alkyl and R⁷ is H or (C₁₋₆ alkyl); Y is O or S;Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from: COOHand —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; R⁶ is H, halogen, (C₁₋₆ alkyl) orOR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ is selected from the groupconsisting of 5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl,phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃, 9- or10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂; R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is aninteger from 1 to 4; —CONH(C₆₋₁₀) aryl-5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH,wherein p is an integer from 1 to 4; —O(CH₂)_(p)tetrazolyl, wherein p isan integer from 1 to 4; and n is zero or 1; or a detectable derivativethereof; wherein the detectable derivative is selected from a compoundof the formula (I) labeled with a fluorescent label or a colorimetriclabel; and with the proviso that when n=0 and Y=O, then Z is not OH orOR³, wherein R³ is H, (C₁₋₆)alkyl or (C₆₋₁₀)aryl(C₁₋₆)alkyl, whereinsaid alkyl and said aryl are optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₁₋₆)alkyl-hydroxy, halogen,(C₁₋₆)alkylamino, di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl and(CH₂)_(p)COOH in which p is an integer from 1 to 4; and with the provisothat when n=0 and Y=O, then Z is not OR³ wherein R³ is(C₆₋₁₀)aryl(C₁₋₆)alkyl, optionally substituted with from 1 to 4substituents selected from the group consisting of: cyano, NO₂, —COCH₃,—CONH₂, —NH₂, sulfonamido, —SO₂CH₃, —NHSO₂CH₃ and (C₁₋₄)alkoxy; and withthe proviso that when n=0 and Y=O, then Z is not NH₂, NMeR³ or NHR³,wherein R³ is H, or (C₁₋₆)alkyl optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino and di-(C₁₋₆)alkyl-amino; andwith the proviso that when n=1 and Y=O, then Z is not OH or OR³ whereinR³ is (C₁₋₆)alkyl.
 36. A method of inhibiting the replication of thehepatitis C virus, comprising contacting said virus with a compound ofthe following formula I or a pharmaceutically acceptable salt thereof:

wherein: X is CH and A is N; or X is N and A is COR⁷ or CR⁵, wherein R⁵is H, halogen, or (C₁₋₆) alkyl and R⁷ is H or (C₁₋₆ alkyl); Y is O or S;Z is OH, NH₂, NMeR³, NHR₃; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from: COOHand —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; R⁶ is H, halogen, (C₁₋₆ alkyl) orOR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ is selected from the groupconsisting of 5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl,phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃, 9- or10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₄)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂; R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH,—NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH , tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is aninteger from 1 to 4; —CONH(C₆₋₁₀) aryl-5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH,wherein p is an integer from 1 to 4; —O(CH₂)_(p)tetrazolyl, wherein p isan integer from 1 to 4; and n is zero or 1; or a detectable derivativethereof; wherein the detectable derivative is selected from a compoundof the formula (I) labeled with a fluorescent label or a colorimetriclabel; and with the proviso that when n=0 and Y=O, then Z is not OH orOR³, wherein R³ is H, (C₁₋₆)alkyl or (C₆₋₁₀)aryl(C₁₋₆)alkyl, whereinsaid alkyl and said aryl are optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, (C₁₋₆)alkyl, (C₁₋₆)alkyl-hydroxy, halogen,(C₁₋₆)alkylamino, di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl and(CH₂)_(p)COOH in which p is an integer from 1 to 4; and with the provisothat when n=0 and Y=O, then Z is not OR³ wherein R³ is(C₆₋₁₀)aryl(C₁₋₆)alkyl, optionally substituted with from 1 to 4substituents selected from the group consisting of: cyano, NO₂, —COCH₃,—CONH₂, —NH₂, sulfonamido, —SO₂CH₃, —NHSO₂CH₃ and (C₁₋₄)alkoxy; and withthe proviso that when n=0 and Y=O, then Z is not NH₂, NMeR³ or NHR³,wherein R³ is H, or (C₁₋₆)alkyl optionally substituted with from 1 to 4substituents selected from the group consisting of: OH, COOH,COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino and di-(C₁₋₆)alkyl-amino; andwith the proviso that when n=1 and Y=O, then Z is not OH or OR³ whereinR³ is (C₁₋₆)alkyl.
 37. A method of treating HCV infection in a mammal,comprising giving written or oral instructions to administer a compoundof the following formula I or a pharmaceutically acceptable salt thereofto a mammal in need of such treatment:

wherein: X is CH and A is N; or X is N and A is COR⁷ or CR⁵, wherein R⁵is H, halogen, or (C₁₋₆) alkyl and R⁷ is H or (C₁₋₆ alkyl); Y is O or S;Z is OH, NH₂, NMeR³, NHR³; OR³ or 5- or 6-membered heterocycle, having 1to 4 heteroatoms selected from O, N and S, said heterocycle beingoptionally substituted with from 1 to 4 substituents selected from: COOHand —O(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH; R⁶ is H, halogen, (C₁₋₆ alkyl) orOR⁷, wherein R⁷ is H or (C₁₋₆ alkyl); R¹ is selected from the groupconsisting of 5- or 6-membered heterocycle having 1 to 4 heteroatomsselected from O, N, and S, phenyl, phenyl(C₁₋₃)alkyl, (C₂₋₆)alkenyl,phenyl(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₁₋₆)alkyl, CF₃, 9- or10-membered heterobicycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said heterocycle, phenyl, phenyl(C₂₋₆)alkenyl andphenyl(C₁₋₃)alkyl), alkenyl, cycloalkyl, (C₁₋₆)alkyl, and heterobicycleare all optionally substituted with from 1 to 4 substituents selectedfrom: OH, halogen, CF₃, amino, cyano, phenyl(C₁₋₄)alkoxy, COOH,—OCH₂CONHCH₂Ph, (C₁₋₄)alkyl, —OCH₂CONH(CH₂)₂₋₃N(CH₃)₂, (C₁₋₆)alkoxy,—OCH₂CO-(morpholino), pyrrolidinyl, carboxy(C₂₋₄)alkenyl, phenoxy,—NH(C₂₋₄)acyl, —O(CH₂)_(m)OH, m being an integer from 2 to 4, SO₃, andNO₂; R² is selected from (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, (C₆₋₁₀)bicycloalkyl, norbornane, phenyl,and pyridyl, all of which is optionally substituted with from 1 to 4substituents selected from halogen, (C₁₋₆)alkyl, —CH₂OH, O-benzyl andOH; R³ is selected from H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₆₋₁₀)aryl, (C₆₋₁₀)aryl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl(C₂₋₆)alkenyl, (C₆₋₁₀)aryl(C₂₋₆)alkenyl,N{(C₁₋₆) alkyl}₂, NHCOO(C₁₋₆)alkyl(C₆₋₁₀)aryl, NHCO(C₆₋₁₀)aryl,(C₁₋₆)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatomsselected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl,aryl, alkenyl and heterocycle are all optionally substituted with from 1to 4 substituents selected from: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C₂₋₄)alkenyl,(C₂₋₄)alkenyl-(C₁₋₆)alkyl-COOH, and carboxy(C₂₋₄)alkenyl, 5- or6-membered heterocycle having 1 to 4 heteroatoms selected from O, N andS, said heterocycle being optionally substituted with from 1 to 4substituents selected from: (C₁₋₆ alkyl), CF₃, OH, (CH₂)_(p)COOH, COOH,NHCH(C₁₋₆alkyl)₂, NHCO(C₁₋₆ alkyl), NH₂, NH(C₁₋₆ alkyl), and N(C₁₋₆alkyl)₂, wherein p is an integer from 1 to 4; 9- or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂,—COCH₃, (C₁₋₃)alkyl, (C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂,triazolyl, OH, NO₂, NH₂, —O(CH₂)_(p)COOH, hydantoin, benzoyleneurea,(C₁₋₄)alkoxy, cyano, azido, —O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkylCOO—(C₁₋₆)alkyl, —NHCOCOOH, —NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃,—NHCO(C₁₋₆)alkyl-COOH, —NHCOCONH(C₁₋₆)alkyl-COOH,—NHCO(C₃₋₇)cycloalkyl-COOH, —NHCONH(C₆₋₁₀)aryl-COOH,—NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl, —NHCONH(C₁₋₆)alkyl-COOH,—NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; 6- or 10-membered aryl beingoptionally substituted with from 1 to 4 substituents selected from:halogen, OPO₃H, sulfonamido, SO₃H, SO₂CH₃, —CONH₂, —COCH₃, (C₁₋₃)alkyl,(C₂₋₄alkenyl)COOH, tetrazolyl, COOH, —CONH₂, triazolyl, OH, NO₂, NH₂,—O(CH₂)_(p)COOH, hydantoin, benzoyleneurea, (C₁₋₄)alkoxy, cyano, azido,—O—(C₁₋₆)alkyl COOH, —O—(C₁₋₆)alkyl COO—(C₁₋₆)alkyl, —NHCOCOOH,—NHCOCONHOH,—NHCOCONH₂, —NHCOCONHCH₃, —NHCO(C₁₋₆)alkyl-COOH,—NHCOCONH(C₁₋₆)alkyl-COOH, —NHCO(C₃₋₇)cycloalkyl-COOH,—NHCONH(C₆₋₁₀)aryl-COOH, —NHCONH(C₆₋₁₀)aryl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-COOH, —NHCONH(C₁₋₆)alkyl-COO(C₁₋₆)alkyl,—NHCONH(C₁₋₆)alkyl-(C₂₋₆)alkenyl-COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-O(C₁₋₆)alkyl COOH,—NH(C₁₋₆)alkyl-(C₆₋₁₀)aryl-COOH, —NHCH₂COOH, —NHCONH₂,—NHCO(C₁₋₆)hydroxyalkyl COOH, —OCO(C₁₋₆)hydroxyalkyl COOH,(C₃₋₆)cycloalkyl COOH,

 —NHCN, —NHCHO, —NHSO₂CH₃, and —NHSO₂CF₃; coumarin, (C₁₋₆)alkyl-amino,di-(C₁₋₆)alkyl-amino, C(halogen)₃, —NH(C₂₋₄)acyl, —NH(C₆₋₁₀)aroyl,—CONHCH(CH₂OH)₂, —CO(C₁₋₆)alkyl-COOH, —CO—NH-alanyl, —(CH₂)_(p)COOH,—OCH₂Ph, —CONHbenzyl, —CONHpyridyl, —CONHCH₂pyridyl,—CONH(C₂₋₄)alkylN(C₁₋₆alkyl)₂, —CONH(C₂₋₄) alkyl-morpholino, —CONH(C₂₋₄)alkyl-pyrrolidino, —CONH(C₂₋₄) alkyl-N-methylpyrrolidino, —CONH(C₂₋₄)alkyl(COOH)-imidazole, —CONHCH₂CH(OH)CH₂OH, —CONH(C₁₋₆) alkyl-COOH,—CONH(C₆₋₁₀) aryl-COOH, —CONH(C₆₋₁₀) aryl-COO(C₁₋₆) alkyl, —CONH(C₁₋₆)alkyl-COO(C₁₋₆) alkyl, —CONH(C₆₋₁₀) aryl-(C₁₋₆)alkyl-COOH, —CONH(C₆₋₁₀)aryl-(C₂₋₆)alkenyl-COOH, —CONH(C₂₋₆) alkyl-CONH-9 or 10-memberedheterobicycle having 1 to 4 heteroatoms selected from O, N, and S, saidheterobicycle being optionally substituted with from 1 to 4 substituentsselected from: COOH, (C₆₋₁₀)aryl and (CH₂)_(p)COOH, wherein p is aninteger from 1 to 4; —CONH(C₆₋₁₀) aryl-5- or 6-membered heterocyclehaving 1 to 4 heteroatoms selected from O, N and S, said heterocyclebeing optionally substituted with from 1 to 4 substituents selectedfrom: COOH and (CH₂)_(p)COOH, wherein p is an integer from 1 to 4;—CONH(C₁₋₆alkyl)CONH(C₆₋₁₀aryl), said aryl being optionally substitutedwith from 1 to 4 substituents selected from: COOH and (CH₂)_(p)COOH,wherein p is an integer from 1 to 4; —O(CH₂)_(p)tetrazolyl, wherein p isan integer from 1 to 4; and n is zero or 1; and with the proviso thatwhen n=0 and Y=O, then Z is not OH or OR³, wherein R³ is H, (C₁₋₆)alkylor (C₆₋₁₀)aryl(C₁₋₆)alkyl, wherein said alkyl and said aryl areoptionally substituted with from 1 to 4 substituents selected from thegroup consisting of: OH, COOH, COO(C₁₋₆)alkyl, (C₁₋₆)alkyl,(C₁₋₆)alkyl-hydroxy, halogen, (C₁₋₆)alkylamino, di-(C₁₋₆)alkyl-amino,C(halogen)₃, —NH(C₂₋₄)acyl and (CH₂)_(p)COOH in which p is an integerfrom 1 to 4; and with the proviso that when n=0 and Y=O, then Z is notOR³ wherein R³ is(C₆₋₁₀)aryl(C₁₋₆)alkyl, optionally substituted withfrom 1 to 4 substituents selected from the group consisting of: cyano,NO₂, —COCH₃, —CONH₂, —NH₂, sulfonamido, —SO₂CH₃, —NHSO₂CH₃ and(C₁₋₄)alkoxy; and with the proviso that when n=0 and Y=O, then Z is notNH₂, NMeR³ or NHR³, wherein R³ is H, or (C₁₋₆)alkyl optionallysubstituted with from 1 to 4 substituents selected from the groupconsisting of: OH, COOH, COO(C₁₋₆)alkyl, halogen, (C₁₋₆)alkylamino anddi-(C₁₋₆)alkyl-amino; and with the proviso that when n=1 and Y=O, then Zis not OH or OR³ wherein R³ is (C₁₋₆)alkyl.